Drug cores for sustained release of therapeutic agents

ABSTRACT

A solid drug core insert can be manufactured by injecting a liquid mixture comprising a therapeutic agent and a matrix precursor into a sheath body. The injection can be conducted at subambient temperatures. The mixture is cured to form a solid drug-matrix core. The therapeutic agent can be a liquid at about room temperature that forms a dispersion of droplets in the matrix material. A surface of the solid drug core is exposed, for example by cutting the tube, and the exposed surface of the solid drug core releases therapeutic quantities of the therapeutic agent when implanted into the patient. In some embodiments, the insert body inhibits release of the therapeutic agent, for example with a material substantially impermeable to the therapeutic agent, such that the therapeutic quantities are released through the exposed surface, thereby avoiding release of the therapeutic agent to non-target tissues.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation application under 35 U.S.C. §120 ofU.S. patent application Ser. No. 12/231,986, filed Sep. 5, 2008, whichclaims the benefit of priority under 35 U.S.C. §119(e) to U.S.Provisional Patent Application Ser. Nos. 60/970,699, filed Sep. 7, 2007;60/970,709, filed Sep. 7, 2007; 60/970,820, filed Sep. 7, 2007; and61/049,317, filed Apr. 30, 2008, which are all incorporated herein byreference in their entireties.

The subject matter of this application is related to that of U.S. patentapplication Ser. No. 11/695,537, filed on Apr. 2, 2007, published asU.S. Patent Application Publication No. 2007/0269487 on Nov. 22, 2007,which claims the benefit of U.S. Provisional Application No. 60/871,864,filed on Dec. 26, 2006, the disclosures of which are incorporated hereinby reference in their entireties.

The subject matter of this application is related to that of U.S. Pat.App. No. 61/057,246, filed on May 30, 2008 and U.S. Pat. App. No.61/132,927, filed on Jun. 24, 2008, and U.S. patent application Ser. No.12/231,989, filed Sep. 8, 2008, entitled “LACRIMAL IMPLANTS AND RELATEDMETHODS,” and published as U.S. Patent Application Publication No.2009/0104248 on Apr. 23, 2009.

BACKGROUND

A variety of challenges face patients and physicians in the area of drugdelivery, for example, ocular drug delivery. In particular, therepetitive nature of the therapies (multiple injections, instillingmultiple eye drop regimens per day), the associated costs, and the lackof patient compliance may significantly impact the efficacy of thetherapies available, leading to reduction in vision and many timesblindness.

Patient compliance in taking the medications, for example, instillingthe eye drops, can be erratic, and in some cases, patients may notfollow the directed treatment regime. Lack of compliance can include,failure to instill the drops, ineffective technique (instilling lessthan required), excessive use of the drops (leading to systemic sideeffects), and use of non-prescribed drops or failure to follow thetreatment regime requiring multiple types of drops. Many of themedications may require the patient to instill them up to 4 times a day.

In addition to compliance, the cost of at least some eye dropmedications is increasing, leading some patients on limited incomes tobe faced with the choice of buying basic necessities or instead gettingtheir prescriptions filled. Many times insurance does not cover thetotal cost of the prescribed eye drop medication, or in some cases eyedrops containing multiple different medications.

Further, in many cases, topically applied medications have a peak oculareffect within about two hours, after which additional applications ofthe medications should be performed to maintain the therapeutic benefit.In addition, inconsistency in self-administered or ingested medicationregimes can result in a suboptimal therapy. PCT Publication WO 06/014434(Lazar), which is incorporated herein by reference in its entirety, maybe relevant to these and/or other issues associated with eye drops.

One promising approach to ocular drug delivery is to place an implantthat releases a drug in tissue near the eye. Although this approach canoffer some improvement over eye drops, some potential problems of thisapproach may include implantation of the implant at the desired tissuelocation, retention of the implant at the desired tissue location, andsustaining release of the drug at the desired therapeutic level for anextended period of time. For example in the case of glaucoma treatment,visits to the treating physician can be months apart, and prematuredepletion and/or premature release of a drug from an implant can resultin insufficient drug being delivered for a portion of the treatmentperiod. This can result in the patient potentially suffering a reductionin vision or blindness.

In light of the above, it would be desirable to provide for themanufacture of improved drug delivery implants that overcome at leastsome of the above mentioned shortcomings.

SUMMARY

The present invention is directed to various embodiments of drug insertsand drug cores containing therapeutic agents for use in implant bodiesadapted for disposition in a body tissue, fluid, cavity, or duct. Theimplant bodies can be adapted to be disposed in or adjacent to an eye ofa patient. The implants release the agent to the body, for example, intoan eye or surrounding tissues, or both, over a period of time, fortreatment of a malcondition in the patient for which use of thetherapeutic agent is medically indicated. The invention is also directedto various embodiments of methods of manufacture of the drug inserts anddrug cores, and to methods of treatment of patients using implantscontaining the drug inserts or drug inserts.

In various embodiments, the invention provides a drug insert adapted fordisposition within an implant, the implant being adapted for dispositionwithin or adjacent to an eye of a patient, the drug insert comprising adrug core that can include a sheath body partially covering the drugcore, the drug core comprising a therapeutic agent and a matrix whereinthe matrix comprises a polymer, the sheath body being disposed over aportion of the drug core to control the release of the agent from saidportion and so as to define at least one exposed surface of the drugcore adapted to release the agent, or any combination thereof, when theimplant is inserted into the patient, wherein an amount of thetherapeutic agent in a volumetric portion of the drug core is similar toan amount of the therapeutic agent in any other equal volumetric portionof the drug core. For example, the therapeutic agent may be uniformlyand homogeneously dispersed throughout the matrix, or the therapeuticagent at least in part forms solid or liquid inclusions within thematrix. For example, the amount of the therapeutic agent within thevolumetric portion of the drug core may vary from the amount of thetherapeutic agent within any other equal volumetric portion of the drugcore by no greater than about 30%. For example, the amount of thetherapeutic agent within the volumetric portion of the drug core variesfrom the amount of the therapeutic agent within any other equalvolumetric portion of the drug core by no greater than about 20%. Forexample, the amount of the therapeutic agent within the volumetricportion of the drug core varies from the amount of the therapeutic agentwithin any other equal volumetric portion of the drug core by no greaterthan about 10%. For example, the amount of the therapeutic agent withinthe volumetric portion of the drug core varies from the amount of thetherapeutic agent within any other equal volumetric portion of the drugcore by no greater than about 5%. For example, the amount of thetherapeutic agent within a volumetric portion of the drug core is thesame as the amount of the therapeutic agent within any other equalvolumetric portion of the drug core. In various embodiments, the druginsert can be adapted to release the agent to the eye, surroundingtissues, systemically, or any combination thereof, and/or for providingsustained release of a therapeutic agent to the eye or surroundingtissues, or systemically, or any combination thereof.

In various embodiments, the invention provides a plurality of the druginserts as described above wherein each of the plurality of the insertscomprises a similar amount of the agent dispersed respectivelytherewithin. For example, the similar amount of agent dispersedrespectively therein can vary no greater than about 30% therebetween.For example, the similar amount of agent dispersed respectively thereincan vary no greater than about 20% therebetween. For example, thesimilar amount of agent dispersed respectively therein can vary nogreater than about 10% therebetween. For example, the similar amount ofagent dispersed respectively therein can vary no greater than about 5%therebetween.

In various embodiments, the invention provides a drug core comprising atherapeutic agent and a matrix wherein the matrix comprises a polymer,for disposition into a drug insert or an implant, the drug insert or theimplant being adapted for disposition within or adjacent to an eye of apatient, wherein the therapeutic agent is uniformly homogeneouslydispersed throughout the matrix, or the therapeutic agent at least inpart forms solid or liquid inclusions within the matrix; wherein anamount of the therapeutic agent in a volumetric portion of the drug coreis similar to an amount of the therapeutic agent in any other equalvolumetric portion of the drug core. For example, the amount of thetherapeutic agent in a volumetric portion of the drug core can vary fromthe amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 30%. For example, theamount of the therapeutic agent in a volumetric portion of the drug corecan vary from the amount of the therapeutic agent in any other equalvolumetric portion of the drug core by no greater than about 20%. Forexample, the amount of the therapeutic agent in a volumetric portion ofthe drug core can vary from the amount of the therapeutic agent in anyother equal volumetric portion of the drug core by no greater than about10%. For example, the amount of the therapeutic agent in a volumetricportion of the drug core can vary from the amount of the therapeuticagent in any other equal volumetric portion of the drug core by nogreater than about 5%. For example, the amount of the therapeutic agentwithin a volumetric portion of the drug core is the same as the amountof the therapeutic agent within any other equal volumetric portion ofthe drug core. In various embodiments, the drug insert can be adapted torelease the agent to the eye, surrounding tissues, systemically, or anycombination thereof, and/or for providing sustained release of atherapeutic agent to the eye or surrounding tissues, or systemically, orany combination thereof.

In various embodiments, the invention provides an implant for sustaineddelivery of a therapeutic agent to a patient, wherein the entire implantcomprises a drug core comprising a therapeutic agent and a matrix,wherein the matrix comprises a polymer. A porous or absorbent materialcan alternatively be used to make up the entire implant or plug whichcan be saturated with the active agent.

In various embodiments, the invention provides a filled precursor sheathadapted for manufacture of a plurality of drug inserts therefrom bydivision of the filled precursor sheath, each drug insert being adaptedfor disposition within a respective implant, the implant being adaptedfor disposition within or adjacent to an eye of a patient, the filledprecursor sheath comprising a precursor sheath body and a precursor drugcore contained therewithin, the precursor drug core comprising atherapeutic agent and a matrix wherein the matrix comprises a polymer,wherein the therapeutic agent is uniformly and homogeneously dispersedthroughout the matrix, or the therapeutic agent at least in part formssolid or liquid inclusions within the matrix, wherein an amount of thetherapeutic agent in a volumetric portion of the precursor drug core issimilar to an amount of the therapeutic agent in any other equalvolumetric portion of the precursor drug core, the precursor sheath bodybeing substantially impermeable to the agent, each of the plurality ofinserts divided therefrom being adapted to release the agent, arespective sheath body of each of the plurality of inserts divided fromthe filled precursor sheath being disposed over a portion of arespective drug core of each of the plurality of inserts to inhibitrelease of the agent from said portion and so as to define at least oneexposed surface of the drug core adapted to release the agent, when theinsert is disposed in an implant and the implant is inserted into thepatient. For example, an amount of the therapeutic agent in a volumetricportion of the precursor drug core can vary from an amount of thetherapeutic agent in any other equal volumetric portion of the precursordrug core by no greater than about 30%. For example, an amount of thetherapeutic agent in a volumetric portion of the precursor drug core canvary from an amount of the therapeutic agent in any other equalvolumetric portion of the precursor drug core by no greater than about20%. For example, an amount of the therapeutic agent in a volumetricportion of the precursor drug core can vary from an amount of thetherapeutic agent in any other equal volumetric portion of the precursordrug core by no greater than about 10%. For example, an amount of thetherapeutic agent in a volumetric portion of the precursor drug core canvary from an amount of the therapeutic agent in any other equalvolumetric portion of the precursor drug core by no greater than about5%. For example, the amount of the therapeutic agent within a volumetricportion of the drug core is the same as the amount of the therapeuticagent within any other equal volumetric portion of the drug core. Invarious embodiments, the drug insert can be adapted to release the agentto the eye, surrounding tissues, systemically, or any combinationthereof, and/or for providing sustained release of a therapeutic agentto the eye or surrounding tissues, or systemically, or any combinationthereof.

In various embodiments, the invention provides an implant body fordisposition in or adjacent to an eye of a patient, the implant bodycomprising a channel therein adapted to receive a drug insert such thatan exposed surface of the drug insert will be exposed to tear liquidwhen the drug insert is disposed within the implant and when the implantis disposed in or adjacent to the eye, the drug insert comprising asheath body that is substantially impermeable to the agent, containingtherewithin a drug core comprising a therapeutic agent and a matrixcomprising a polymer, wherein the therapeutic agent is uniformly andhomogeneously dispersed throughout the matrix, or the therapeutic agentat least in part forms solid or liquid inclusions within the matrixwherein an amount of the therapeutic agent in a volumetric portion ofthe drug core is similar to an amount of the therapeutic agent in anyother equal volumetric portion of the drug core, the body comprising abiocompatible material and being adapted to be retained within oradjacent to the eye for a period of time. For example, the amount of thetherapeutic agent in a volumetric portion of the drug core can vary fromthe amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 30%. For example, theamount of the therapeutic agent in a volumetric portion of the drug corecan vary from the amount of the therapeutic agent in any other equalvolumetric portion of the drug core by no greater than about 20%. Forexample, the amount of the therapeutic agent in a volumetric portion ofthe drug core can vary from the amount of the therapeutic agent in anyother equal volumetric portion of the drug core by no greater than about10%. For example, the amount of the therapeutic agent in a volumetricportion of the drug core can vary from the amount of the therapeuticagent in any other equal volumetric portion of the drug core by nogreater than about 5%. For example, the amount of the therapeutic agentwithin a volumetric portion of the drug core is the same as the amountof the therapeutic agent within any other equal volumetric portion ofthe drug core. In various embodiments, the drug insert can be adapted torelease the agent to the eye, surrounding tissues, systemically, or anycombination thereof, and/or for providing sustained release of atherapeutic agent to the eye or surrounding tissues, or systemically, orany combination thereof

In various embodiments, the invention provides an implant body fordisposition in or adjacent to an eye of a patient, the implant bodycomprising a channel therein adapted to receive a drug core such that anexposed surface of the drug core will be exposed to tear liquid when thedrug core is disposed within the implant and when the implant isdisposed in or adjacent to the eye, the drug core comprising atherapeutic agent and a matrix comprising a polymer, wherein an amountof the therapeutic agent in a volumetric portion of the drug core issimilar to an amount of the therapeutic agent in any equal volumetricportion of the drug core, wherein the therapeutic agent is sufficientlysoluble in the matrix such that therapeutic quantities of the agent willbe released from the exposed surface of the drug core to tear liquid incontact with the exposed surface when the implant body is disposed in oradjacent to an eye, the body comprising a biocompatible material andbeing adapted to be retained within or adjacent to the eye for a periodof time. For example, the amount of the therapeutic agent in avolumetric portion of the drug core can vary from the amount of thetherapeutic agent in any equal volumetric portion of the drug core by nogreater than about 30%. For example, the amount of the therapeutic agentin a volumetric portion of the drug core can vary from the amount of thetherapeutic agent in any equal volumetric portion of the drug core by nogreater than about 20%. For example, the amount of the therapeutic agentin a volumetric portion of the drug core can vary from the amount of thetherapeutic agent in any equal volumetric portion of the drug core by nogreater than about 10%. For example, the amount of the therapeutic agentin a volumetric portion of the drug core can vary from the amount of thetherapeutic agent in any equal volumetric portion of the drug core by nogreater than about 5%. In various embodiments, the drug core can beadapted to release the therapeutic agent to the eye, surroundingtissues, systemically, or any combination thereof, and/or for providingsustained release of a therapeutic agent to the eye or surroundingtissues, or systemically, or any combination thereof.

In various embodiments, the invention provides a method of manufacturinga drug insert for an implant body adapted for disposition within oradjacent to an eye of a patient, the insert comprising a drug corecomprising a therapeutic agent and a matrix wherein the matrix comprisesa polymer, wherein the therapeutic agent is uniformly and homogeneouslydispersed throughout the matrix, or the therapeutic agent at least inpart forms solid or liquid inclusions within the matrix wherein anamount of the therapeutic agent in a volumetric portion of the drug coreis similar to an amount of the therapeutic agent in any other equalvolumetric portion of the drug core, the sheath body being disposed overa portion of the drug core to inhibit release of the agent from saidportion and so as to define at least one exposed surface of the drugcore adapted to release the agent when the implant is inserted into thepatient; the method comprising injecting, at a subambient temperature ofless than about 20° C., a mixture comprising a matrix precursor and theagent into the sheath body such that the sheath body is substantiallyfilled therewith; then, curing the mixture comprising the matrixprecursor within the sheath body to form the drug insert such that adrug core having an exposed surface is formed therein. In variousembodiments, the drug insert can be adapted to release the agent to theeye, surrounding tissues, systemically, or any combination thereof,and/or for providing sustained release of a therapeutic agent to the eyeor surrounding tissues, or systemically, or any combination thereof.

In various embodiments, the invention provides a method of manufacturinga drug insert for an implant body adapted for disposition within oradjacent to an eye of a patient, the method comprising injecting, at asubambient temperature of less than about 20° C., a mixture comprising atherapeutic agent and a matrix precursor into a precursor sheath body,wherein the therapeutic agent is uniformly and homogeneously dispersedthroughout the matrix, or the therapeutic agent at least in part formssolid or liquid inclusions within the matrix, wherein an amount of thetherapeutic agent in a volumetric portion of the drug core is similar toan amount of the therapeutic agent in any other equal volumetric portionof the drug core, the precursor sheath body being substantiallyimpermeable to the agent, such that the precursor sheath issubstantially filled therewith to provide a filled precursor sheath;then, curing the mixture such that a precursor drug core is formedwithin the precursor sheath body, and then, dividing the filledprecursor sheath to form a plurality of drug inserts therefrom, whereineach drug insert comprises a drug core and a sheath body, the sheathbody being disposed over a portion of the drug core to inhibit releaseof the agent from said portion and so as to define at least one exposedsurface of the drug core, when the insert is disposed with an implantand the implant is inserted into the patient; each insert being adaptedfit within a respective implant body and to release, through the exposedsurface of the insert, therapeutic quantities of the agent to tearliquid; wherein each of the plurality of drug inserts is ofsubstantially the same length, wherein an amount of the agent in each ofthe plurality of inserts divided from the filled precursor sheath issimilar.

For example, the amount of the therapeutic agent in a volumetric portionof the drug core can vary from the amount of the therapeutic agent inany other equal volumetric portion of the drug core by no greater thanabout 30%. For example, the amount of the therapeutic agent in avolumetric portion of the drug core can vary from the amount of thetherapeutic agent in any other equal volumetric portion of the drug coreby no greater than about 20%. For example, the amount of the therapeuticagent in a volumetric portion of the drug core can vary from the amountof the therapeutic agent in any other equal volumetric portion of thedrug core by no greater than about 10%. For example, the amount of thetherapeutic agent in a volumetric portion of the drug core can vary fromthe amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 5%. For example, theamount of the agent in each of the plurality of inserts can vary by nogreater than about 30% therebetween. For example, the amount of theagent in each of the plurality of inserts can vary by no greater thanabout 20% therebetween. For example, the amount of the agent in each ofthe plurality of inserts can vary by no greater than about 10%therebetween. For example, the amount of the agent in each of theplurality of inserts can vary by no greater than about 5% therebetween.

In further embodiments, the method of manufacturing a drug insertfurther comprises, after the curing step as described herein, extrudingthe drug core from the sheath body prior to or after dividing the filledsheath body into a plurality of drug insert, thereby forming the drugcores free of the sheath body material.

In various embodiments, the above methods are employed to manufacture animplant for sustained delivery of a therapeutic agent to a patient,wherein the entire implant comprises a drug core comprising atherapeutic agent and a matrix, wherein the matrix comprises a polymer.A porous or absorbent material can alternatively be used to make up theentire implant or plug which can be saturated with the active agent. Inother embodiments, a therapeutic agent and a matrix as described hereinare added to a mold to form the drug core; the drug core is then cured,then used as an implant for sustained delivery of the therapeutic agentto a patient.

In various embodiments, the invention provides a drug insert made by amethod of the invention.

In various embodiments, the invention provides a method of treating amalcondition in a patient in need thereof; comprising disposing animplant comprising a drug insert of the invention, or a drug core of theinvention, or a drug core obtained by division of a filled precursorsheath of the invention, or a drug implant of the invention, or a druginsert prepared by the method of the invention, wherein the therapeuticagent is adapted to treat the malcondition, in or adjacent to an eye ofthe patient such that the drug is released into a body tissue or fluid.

In various embodiments, the invention provides the use of a drug insertof the invention, or a drug core of the invention, or a drug coreobtained by division of a filled precursor sheath of the invention, or adrug implant of the invention, or a drug insert prepared by the methodof the invention, in the manufacture of an implant adapted for treatmentof a malcondition in a patient in need thereof.

In various embodiments, the invention provides a drug insert adapted fordisposition within an punctal plug for providing sustained release of alatanoprost to the eye for treatment of glaucoma, the insert comprisinga core and a sheath body partially covering the core, the corecomprising the latanoprost and a matrix wherein the matrix comprises asilicone polymer, the latanoprost being contained within the silicone asdroplets thereof, wherein an amount of the latanoprost in a volumetricportion of the drug core is similar to an amount of the latanoprost inany other equal volumetric portion of the drug core, the sheath bodybeing disposed over a portion of the core to inhibit release of thelatanoprost from said portion, an exposed surface of the core notcovered by the sheath body being adapted to release the latanoprost tothe eye.

In various embodiments, the invention provides a drug insert adapted fordisposition within an punctal plug for providing sustained release of acyclosporine to the eye for treatment of dry eye or inflammation, theinsert comprising a core and a sheath body partially covering the core,the core comprising the cyclosporine and a matrix wherein the matrixcomprises a polyurethane polymer, the cyclosporine being containedwithin the polyurethane, wherein an amount of the cyclosporine in avolumetric portion of the drug core is similar to an amount of thecyclosporine in any other equal volumetric portion of the drug core, thesheath body being disposed over a portion of the core to inhibit releaseof the cyclosporine from said portion, an exposed surface of the corenot covered by the sheath body being adapted to release the cyclosporineto the eye.

In various embodiments, the invention provides a drug insert adapted fordisposition within an implant, the implant being adapted for dispositionwithin or adjacent to a body cavity, tissue, duct, or fluid, forproviding sustained release of a therapeutic agent to the cavity, duct,tissue, or surrounding tissues or any combination thereof, the insertcomprising a drug core and a sheath body partially covering the drugcore, the drug core comprising a therapeutic agent and a matrix whereinthe matrix comprises a polymer, wherein the therapeutic agent isuniformly and homogeneously dispersed throughout the matrix, or thetherapeutic agent at least in part forms solid or liquid inclusionswithin the matrix, wherein an amount of the therapeutic agent in avolumetric portion of the drug core is similar to an amount of thetherapeutic agent in any other equal volumetric portion of the drugcore, the sheath body being disposed over a portion of the drug core toinhibit release of the agent from said portion and so as to define atleast one exposed surface of the drug core adapted to release the agentto the cavity, duct, tissue, or surrounding tissues or any combinationthereof, when the implant is inserted into the patient.

In various embodiments, the invention provides a drug insert adapted fordisposition within an implant, the implant being adapted for dispositionwithin or adjacent to an eye of a patient, for providing sustainedrelease of a therapeutic agent systemically, the insert comprising adrug core and a sheath body partially covering the drug core, the drugcore comprising a therapeutic agent and a matrix wherein the matrixcomprises a polymer, wherein the therapeutic agent is uniformly andhomogeneously dispersed throughout the matrix, or the therapeutic agentat least in part forms solid or liquid inclusions within the matrix,wherein an amount of the therapeutic agent in a volumetric portion ofthe drug core is similar to an amount of the therapeutic agent in anyother equal volumetric portion of the drug core, the sheath body beingdisposed over a portion of the drug core to inhibit release of the agentfrom said portion and so as to define at least one exposed surface ofthe drug core adapted to release the agent systemically when the implantis inserted into the patient.

In various embodiments, the invention provides a drug core comprising atherapeutic agent and a matrix wherein the matrix comprises a polymer,for disposition as or into a drug insert or an implant, the drug insertor the implant being adapted for disposition within or adjacent to abody cavity, tissue, duct, or fluid, for providing sustained release ofa therapeutic agent to the cavity, duct, tissue, or surrounding tissuesor any combination thereof, wherein the therapeutic agent is uniformlyhomogeneously dispersed throughout the matrix, or the therapeutic agentat least in part forms solid or liquid inclusions within the matrix;wherein an amount of the therapeutic agent in a volumetric portion ofthe drug core is similar to an amount of the therapeutic agent in anyother equal volumetric portion of the drug core.

In various embodiments, the invention provides a drug core comprising atherapeutic agent and a matrix wherein the matrix comprises a polymer,for disposition as or into a drug insert or an implant, the drug insertor the implant being adapted for disposition within or adjacent to aneye of a patient for providing sustained release of the therapeuticagent systemically, wherein the therapeutic agent is uniformlyhomogeneously dispersed throughout the matrix, or the therapeutic agentat least in part forms solid or liquid inclusions within the matrix;wherein an amount of the therapeutic agent in a volumetric portion ofthe drug core is similar to an amount of the therapeutic agent in anyother equal volumetric portion of the drug core. The drug core may beformed into an implant or drug insert by molding the matrix with thetherapeutic agent into an appropriate shape. The implant of this formhas no sheath or outer implant body or housing.

Although it is not intended to be a limitation of the invention, it isbelieved the therapeutic agent transports through the matrix to itssurface whereupon the agent becomes dispersed, dissolved or otherwiseentrained with body fluid for delivery to target tissue. The transportmay be the result of and/or influenced by diffusion, molecularinteraction, domain formation and transport, infusion of body fluid intothe matrix or other mechanisms. For delivery to the eye, therapeuticquantities of agent transport to the exposed surface of the matrixwhereupon tear liquid will sweep away the agent for delivery to targettissue or tissues.

To better illustrate the invention described herein, a non-limiting listof exemplary aspects and embodiments of the invention is provided asfollows.

Aspect A1 concerns a drug insert adapted for disposition within animplant, the implant being adapted for disposition within or adjacent toa body cavity, tissue, duct, or fluid, the insert comprising a drug coreand a sheath body partially covering the drug core, the drug corecomprising a therapeutic agent and a matrix, the matrix comprising apolymer, the sheath body being disposed over a portion of the drug coreto inhibit release of the agent from said portion and so as to define atleast one exposed surface of the drug core adapted to release the agentto the cavity, tissue, duct, or fluid, or any combination thereof whenthe implant is inserted into the patient, and wherein an amount of thetherapeutic agent in a volumetric portion of the drug core is similar toan amount of the therapeutic agent in any other equal volumetric portionof the drug core.

Embodiment A2 concerns the drug insert of aspect A1 wherein the amountof the therapeutic agent within the volumetric portion of the drug corevaries from the amount of the therapeutic agent within any other equalvolumetric portion of the drug core by no greater than about 30%.

Embodiment A3 concerns the drug insert of aspect A1 wherein the amountof the therapeutic agent within the volumetric portion of the drug corevaries from the amount of the therapeutic agent within any other equalvolumetric portion of the drug core by no greater than about 20%.

Embodiment A4 concerns the drug insert of aspect A1 wherein the amountof the therapeutic agent within the volumetric portion of the drug corevaries from the amount of the therapeutic agent within any other equalvolumetric portion of the drug core by no greater than about 10%.

Embodiment A5 concerns the drug insert of aspect A1 wherein the amountof the therapeutic agent within the volumetric portion of the drug corevaries from the amount of the therapeutic agent within any other equalvolumetric portion of the drug core by no greater than about 5%.

Embodiment A6 concerns the drug insert of aspect A1 wherein the implantis a punctal plug.

Embodiment A7 concerns a plurality of the drug inserts of aspect A1wherein each of the plurality of the inserts comprises a similarconcentration of the agent relative to the other inserts of theplurality.

Embodiment A8 concerns the plurality of drug inserts of embodiment A7wherein the similar concentration of agent varies no greater than about30% therebetween.

Embodiment A9 concerns the plurality of drug inserts of embodiment A7wherein the similar concentration of agent varies no greater than about20% therebetween.

Embodiment A10 concerns the plurality of drug inserts of embodiment A7wherein the similar concentration of agent varies no greater than about10% therebetween.

Embodiment A11 concerns the plurality of drug inserts of embodiment A7wherein the similar concentration of agent varies no greater than about5% therebetween.

Embodiment A12 concerns the drug insert of aspect A1 wherein the exposedsurface is adapted to release therapeutic quantities of the agent for atime period of at least several days into tear liquid when the implantis inserted into the patient.

Embodiment A13 concerns the plurality of drug inserts of embodiment A7wherein the exposed surface of each of the plurality of drug inserts isadapted to release therapeutic quantities of the agent for a time periodof at least several days into tear liquid when the implant is insertedinto the patient, wherein the therapeutic quantity of the agent releasedby each of the plurality of drug insert is similar.

Embodiment A14 concerns the plurality of embodiment A13, wherein thetherapeutic quantity of the agent released by each of the plurality ofthe inserts varies by no greater than about 30% therebetween.

Embodiment A15 concerns the plurality of embodiment A13, wherein thetherapeutic quantity of the agent released by each of the plurality ofthe inserts varies by no greater than about 20% therebetween.

Embodiment A16 concerns the plurality of embodiment A13, wherein thetherapeutic quantity of the agent released by each of the plurality ofthe inserts varies by no greater than about 10% therebetween.

Embodiment A17 concerns the plurality of embodiment A13, wherein thetherapeutic quantity of the agent released by each of the plurality ofthe inserts varies by no greater than about 5% therebetween.

Embodiment A18 concerns the drug insert of aspect A1 wherein the drugcore comprises about 0.1 wt % to about 50 wt % of the agent.

Embodiment A19 concerns the drug insert of aspect A1 wherein the matrixcomprises a non-biodegradable silicone or a polyurethane, or combinationthereof.

Embodiment A20 concerns the drug insert of aspect A1 wherein the sheathbody comprises a polymer comprising at least one of polyimide, PMMA, orPET, wherein the polymer is extruded or cast; or a metal comprisingstainless steel or titanium.

Embodiment A21 concerns the drug insert of aspect A1 wherein the agentcomprises a glaucoma medication, a muscarinic agent, a beta blocker, analpha agonist, a carbonic anhydrase inhibitor, a prostaglandin orprostaglandin analog; an anti-inflammatory agent; an anti-infectiveagent; a dry eye medication; or any combination thereof.

Embodiment A22 concerns the drug insert of embodiment A21 wherein theanti-inflammatory agent comprises a steroid, a soft steroid, or an NSAIDand other compounds with analgesic properties.

Embodiment A23 concerns the drug insert of embodiment A21 wherein theanti-infective agent comprises an antibiotic, an antiviral, or anantimycotic.

Embodiment A24 concerns the drug insert of embodiment A21 wherein thedry eye medication comprises cyclosporine, antihistamine, mast cellstabilizer such as olapatadine, a demulcent, or sodium hyaluronate.

Embodiment A25 concerns the drug insert of aspect A1 wherein the agentcomprises latanoprost, and the amount of the agent in the drug insert isabout 10-50 μg.

Embodiment A26 concerns the drug insert of aspect A1 wherein the druginsert comprises a release rate modifying material comprising an inertfiller material, a salt, a surfactant, a dispersant, a second polymer,an oligomer, or a combination thereof.

Embodiment A27 concerns the drug insert of aspect A1 wherein the drugcore is substantially cylindrical in form, having an axis, wherein theexposed surface of the drug core is disposed on one end of thecylindrical form and a surface of the drug core covered by the sheathbody constitutes a remainder of the surface of the cylindrical form.

Embodiment A28 concerns the drug insert of aspect A1 wherein the agentis dissolved in the matrix within the drug core.

Embodiment A29 concerns the drug insert of embodiment A28 wherein theagent comprises cyclosporine and the matrix comprises polyurethane.

Embodiment A30 concerns the drug insert of aspect A1 wherein the agentis present at least in part as a plurality of solid or liquid inclusionsthroughout the matrix, the inclusions comprising, at a temperature ofless than about 25° C., droplets of the agent of no greater than about100 μm diameter when the agent is a liquid at less than about 25° C., orparticles of the agent of no greater than about 100 μm diameter when theagent is a solid at less than about 25° C.

Embodiment A31 concerns the drug insert of embodiment A30 wherein anaverage inclusion diameter and a size distribution of a plurality ofinclusion diameters within a population of inclusions have an effect ona rate of release of the agent from the drug core to the patient.

Embodiment A32 concerns the drug insert of embodiment A30 wherein theinclusions have an average diameter of less than about 20 μm.

Embodiment A33 concerns the drug insert of embodiment A32 wherein astandard deviation of diameters of the inclusions is less than about 8μm.

Embodiment A34 concerns the drug insert of embodiment A30 wherein theinclusions have an average diameter of less than about 15 μm.

Embodiment A35 concerns the drug insert of embodiment A34 wherein astandard deviation of diameters of the inclusions is less than about 6μm.

Embodiment A36 concerns the drug insert of embodiment A30 wherein theinclusions have an average diameter of less than about 10 μm.

Embodiment A37 concerns the drug insert of embodiment A36 wherein astandard deviation of diameters of the inclusions is less than about 4μm.

Embodiment A38 concerns the drug insert of embodiment A30 wherein adistribution of diameters of the inclusions is a monodispersedistribution.

Embodiment A39 concerns the drug insert of embodiment A30 wherein theinclusions predominantly comprise a cross-sectional size within a rangefrom about 0.1 μm to about 50 μm.

Embodiment A40 concerns the drug insert of embodiment A30 wherein theagent forms inclusions in the matrix that are in a liquid physical stateat less than about 25° C.

Embodiment A41 concerns the drug insert of embodiment A40 whereinsubstantially all the inclusions are droplets of the agent of less thanabout 30 μm in diameter within the matrix.

Embodiment A42 concerns the drug insert of embodiment A40 wherein thedroplets have an average diameter of less than about 10 μm.

Embodiment A43 concerns the drug insert of embodiment A42 wherein astandard deviation of diameters of the inclusions is less than about 4μm.

Embodiment A44 concerns the drug insert of embodiment A40 wherein theagent is latanoprost.

Embodiment A45 concerns the drug insert of embodiment A30 wherein theagent forms inclusions in the matrix that are in a solid physical stateat less than about 25° C.

Embodiment A46 concerns the drug insert of embodiment A45 whereinsubstantially all the inclusions are particles of the agent of less thanabout 30 μm in diameter within the matrix.

Embodiment A47 concerns the drug insert of embodiment A45 wherein anaverage particle diameter within the matrix is about 5-50 μm.

Embodiment A48 concerns the drug insert of embodiment A45 wherein theagent is bimatoprost, olopatadine, or cyclosporine.

Embodiment A49 concerns the drug insert of aspect A1 wherein the corecomprises two or more therapeutic agents.

Embodiment A50 concerns the drug insert of aspect A1 wherein the drugcore comprises first and second drug cores.

Embodiment A51 concerns the drug insert of embodiment A50 wherein thedrug insert comprises two drug cores disposed within the sheath body, afirst drug core comprising a first agent and a first matrix, and asecond drug core comprising a second agent and a second matrix, whereinthe first agent and the second agent are different, and wherein thefirst matrix and the second matrix are either the same or differ fromeach other; the implant body comprising an aperture adapted to receivethe first and the second cores disposed within the sheath body, the drugcores being adapted to be disposed, within the sheath, within theaperture of the implant body.

Embodiment A52 concerns the drug insert of embodiment A50 wherein thefirst matrix and the second matrix differ from each other with respectto at least one of a composition, an exposed surface area, a surfactant,a crosslinker, an additive, a matrix material, a formulation, a releaserate modifying reagent, or a stability.

Embodiment A53 concerns the drug insert of embodiment A50 wherein thefirst drug core and the second drug core are disposed within the sheathbody such that the first drug core has a surface exposed directly totear liquid and the second drug core does not have a surface exposeddirectly to tear liquid when the drug insert is disposed within theimplant body and the implant body is disposed in or adjacent to the eyeof the patient.

Embodiment A54 concerns the drug insert of embodiment A50 wherein thefirst drug core and the second drug core are disposed side by sidewithin the sheath body.

Embodiment A55 concerns the drug insert of embodiment A50, wherein thefirst drug core and the second drug core are each cylindrical in shapeand disposed with the sheath body, the first drug core being positionednear a proximal end of an aperture in the implant body and the seconddrug core being positioned near a distal end of the aperture, when thedrug insert is disposed within the implant body.

Embodiment A56 concerns the drug insert of embodiment A50, wherein thefirst drug core and the second drug core are each cylindrical in shapeprovided that the first drug core has a first central opening, the drugcores being positioned concentrically within the sheath body within anaperture of the implant body adapted to receive the drug insert, and thesecond drug core being configured to fit within the first centralopening of the first drug core.

Embodiment A57 concerns the drug insert of embodiment A56 wherein thefirst and second drug cores are concentrically positioned within theaperture of the implant body, the first drug core having a first centralopening exposing a first inner surface and the second drug core having asecond central opening exposing a second inner surface, the second drugcore being configured to fit within the first central opening of thefirst drug core, and wherein the aperture extends from a proximal end toa distal end of the implant body thereby being adapted to allow tearliquid to pass through the aperture and contact the first and secondinner surfaces of the first and second central openings and release thefirst and second therapeutic agents into a canaliculus of the patientwhen the implant body is inserted into a patient.

Embodiment A58 concerns the drug insert of embodiment A50 wherein thefirst therapeutic agent has a release profile wherein the first agent isreleased at therapeutic levels throughout a first time period and thesecond therapeutic agent has a second release profile wherein the secondagent is released at therapeutic levels throughout a second time period.

Embodiment A59 concerns the drug insert of embodiment A58 wherein thefirst time period and the second time period are between one week andfive years.

Embodiment A60 concerns the drug insert of embodiment A58 wherein thefirst release profile and the second release profile are substantiallythe same.

Embodiment A61 concerns the drug insert of embodiment A58 wherein thefirst release profile and the second release profile are different.

Embodiment A62 concerns the drug insert of embodiment A50 wherein anyinclusions in the first drug core and in the second drug corerespectively have an average diameter of less than about 20 μm.

Embodiment A63 concerns the drug insert of embodiment A50 wherein anyinclusions in the first drug core and in the second drug corerespectively have a standard deviation of diameters of less than about 8μm.

Embodiment A64 concerns the drug insert of embodiment A50 wherein theimplant body comprises a central bore that extends from a proximal endto a distal end of the implant body so as to be adapted to allow a tearliquid to pass through the implant body and the first and secondtherapeutic agents are released into the tear liquid into a canaliculusof the patient when the implant body is disposed in or adjacent to theeye.

Embodiment A65 concerns the drug insert of embodiment A50 wherein thefirst agent provides a first effect and a side effect to the patient,and the second agent provides a second effect that mitigates or countersthe side effect of the first agent.

Embodiment A66 concerns the drug insert of embodiment A50, furthercomprising disposing a medication-impregnated porous material within thefirst matrix, the second matrix, or both, wherein themedication-impregnated porous material is adapted so as to permit tearliquid to release the first agent, the second agent, or both, from themedication-impregnated porous material at therapeutic levels over asustained period when a drug core-containing implant is disposed withina punctum, and wherein the medication-impregnated porous material is agel material that can swell from a first diameter to a second diameterwhen in contact with tear liquid.

Embodiment A67 concerns the drug insert of embodiment A66 wherein inwhich the second diameter is about 50% greater than the first diameter.

Embodiment A68 concerns the drug insert of embodiment A66 wherein themedication-impregnated porous material is a HEMA hydrophilic polymer.

Embodiment A69 concerns the drug insert of aspect A1 wherein the matrixcomprises a polyurethane polymer or copolymer.

Embodiment A70 concerns the drug insert of embodiment A69 wherein thepolyurethane polymer or copolymer comprises an aliphatic polyurethane,an aromatic polyurethane, a polyurethane hydrogel-forming material, ahydrophilic polyurethane, or a combination thereof.

Embodiment A71 concerns the drug insert of embodiment A69 wherein thepolyurethane polymer or copolymer comprises a hydrogel adapted to swellwhen contacted with an aqueous medium and the sheath body is adapted tobe of sufficient elasticity to expand in response thereto.

Embodiment A72 concerns the drug insert of embodiment A71 wherein theswelling is adapted to retain the implant body within a punctal canal ofthe patient.

Embodiment A73 concerns the drug insert of embodiment A69 wherein thetherapeutic agent comprises cyclosporine or olopatadine, a prodrug or aderivative of cyclosporine or olopatadine, or any combination thereof.

Embodiment A74 concerns the drug insert of embodiment A73 wherein aweight ratio of the cyclosporine or the olopatadine, or the cyclosporineprodrug or derivative, or the olopatadine prodrug or derivative, or thecombination thereof, to the polyurethane polymer or copolymer is about 1wt % to about 70 wt %.

Embodiment A75 concerns the drug insert of aspect A1 wherein aconcentration of the agent in the core is similar in a portion of thedrug core proximate to the exposed surface, a portion distal to theexposed surface, and a portion disposed between the proximate portionand the distal portion.

Embodiment A76 concerns the drug insert of embodiment A75 wherein theproximal portion is in length at least about one tenth a length of thedrug core.

Embodiment A77 concerns the drug insert of aspect A1 wherein the druginsert or the implant is adapted for disposition within or adjacent toan eye of a patient.

Embodiment A78 concerns the drug insert of aspect A1 wherein: a) thetherapeutic agent is uniformly and homogeneously dispersed throughoutthe matrix; or b) the therapeutic agent at least in part forms solid orliquid inclusions within the matrix.

The drug insert aspects and embodiments of aspect A1 and embodiments A2through A76 can be combined in any manner, as long as the combination isnot internally inconsistent. For example, embodiment A6 may be combinedwith any of embodiments A2 through A5. These combinations are intendedto provide the same concepts and meanings as multiply-dependent claimshave and also the concepts and meanings that multiply-dependent claimsupon other multiply-dependent claims have, so that any and allcombinations of preceding and succeeding subject matter are included forthis aspect and embodiment set.

Aspect B1 concerns a drug core comprising a therapeutic agent and amatrix for disposition into or as a drug insert or an implant, the druginsert or the implant being adapted for disposition within or adjacentto a body cavity, tissue, duct, or fluid of a patient, the matrixcomprising a polymer, wherein an amount of the therapeutic agent in avolumetric portion of the drug core is similar to an amount of thetherapeutic agent in any other equal volumetric portion of the drugcore.

Embodiment B2 concerns a drug core of aspect B1 wherein the drug insertor the implant is adapted for disposition within or adjacent to an eyeof a patient.

Embodiment B3 concerns a core of aspect B1 wherein: a) the therapeuticagent is uniformly and homogeneously dispersed throughout the matrix; orb) the therapeutic agent at least in part forms solid or liquidinclusions within the matrix.

Embodiment B4 concerns the drug core of aspect B1, wherein the amount ofthe therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 30%.

Embodiment B5 concerns the drug core of aspect B1, wherein the amount ofthe therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 20%.

Embodiment B6 concerns the drug core of aspect B1, wherein the amount ofthe therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 10%.

Embodiment B7 concerns the drug core of aspect B1, wherein the amount ofthe therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 5%.

Embodiment B8 concerns the drug core of aspect B1, wherein thetherapeutic agent is uniformly homogeneously distributed throughout thematrix.

Embodiment B9 concerns the drug core of aspect B1, wherein thetherapeutic agent at least in part forms solid or liquid inclusionswithin the matrix.

Embodiment B10 concerns the drug core of aspect B1, wherein thetherapeutic agent at least in part forms solid or liquid inclusionswithin the matrix, wherein the inclusions have an average diameter ofless than about 20 μm.

Embodiment B11 concerns the drug core of embodiment B10 wherein astandard deviation of diameters of the inclusions is less than about 8μm.

Embodiment B12 concerns the drug core of aspect B1, wherein thetherapeutic agent at least in part forms solid or liquid inclusionswithin the matrix, wherein the inclusions have an average diameter ofless than about 10 μm.

Embodiment B13 concerns the drug core of embodiment B12 wherein astandard deviation of diameters of the inclusions is less than about 4μm.

Embodiment B14 concerns the drug core of aspect B1, wherein the amountsof the therapeutic agent in equal volumetric portions at about theproximal portion, at about the middle portion and at about the distalportion of the drug core are similar.

Embodiment B15 concerns the drug core of embodiment B14, wherein theamounts of the therapeutic agent vary by no greater than about 30%.

Embodiment B16 concerns the drug core of embodiment B14, wherein theamounts of the therapeutic agent vary by no greater than about 20%.

Embodiment B17 concerns the drug core of embodiment B14, wherein theamounts of the therapeutic agent vary by no greater than about 10%.

Embodiment B18 concerns the drug core of embodiment B16, wherein theamounts vary by no greater than about 5%.

Embodiment B19 concerns the drug core of aspect B1, wherein the polymercomprises a non-biodegradable silicone or polyurethane, or combinationthereof.

Embodiment B20 concerns the drug core of aspect B1, wherein thetherapeutic agent comprises a glaucoma medication, a muscarinic agent, abeta blocker, an alpha agonist, a carbonic anhydrase inhibitor, aprostaglandin or prostaglandin analog; an anti-inflammatory agent; ananti-infective agent; a dry eye medication; or any combination thereof.

Embodiment B21 concerns the drug core of embodiment B20 wherein theanti-inflammatory agent comprises a steroid, a soft steroid, or an NSAIDand/or other compounds with analgesic properties.

Embodiment B22 concerns the drug core of embodiment B20 wherein theanti-infective agent comprises an antibiotic, an antiviral, or anantimycotic.

Embodiment B23 concerns the drug core of embodiment B20 wherein the dryeye medication comprises cyclosporine, antihistamines and mast cellstabilizers, olapatadine, a demulcent, or sodium hyaluronate.

Embodiment B24 concerns the drug core of aspect B1, wherein the polymercomprises silicone.

Embodiment B25 concerns the drug core of aspect B1, wherein thetherapeutic agent comprises cyclosporine and the polymer comprises apolyurethane.

Embodiment B26 concerns the drug core of aspect B1 comprising a releaserate modifying material comprising an inert filler material, a salt, asurfactant, a dispersant, a second polymer, an oligomer, or acombination thereof.

Embodiment B27 concerns the drug core of aspect B1 disposed within asheath body.

Embodiment B28 concerns the drug core of aspect B1 which has been formedinto a shape of an implant body for disposition in or adjacent to a bodycavity, tissue, duct, or fluid of a patient.

The drug core aspects and embodiments of aspect B1 and embodiments B2through B28 can be combined in any manner, as long as the combination isnot internally inconsistent. For example, embodiment B6 may be combinedwith any of embodiments B2 through B5. These combinations are intendedto provide the same concepts and meanings as multiply-dependent claimshave and also the concepts and meanings that multiply-dependent claimsupon other multiply-dependent claims have, so that any and allcombinations of preceding and succeeding subject matter are included forthis aspect and embodiment set.

Aspect C1 concerns a filled precursor sheath comprising a precursorsheath body containing a precursor drug core, the drug core comprising atherapeutic agent and a matrix, the matrix comprising a polymer, theprecursor sheath body being substantially impermeable to the agent,wherein an amount of the therapeutic agent in a volumetric portion ofthe precursor drug core is similar to an amount of the therapeutic agentin any other equal volumetric portion of the precursor drug core.

Embodiment C2 concerns the filled precursor sheath of aspect C1 adaptedfor manufacture of a plurality of drug inserts by division of the filledprecursor sheath, each drug insert being adapted for disposition withina respective implant, the implant being adapted for disposition withinor adjacent a body cavity, tissue, duct or fluid.

Embodiment C3 concerns the filled precursor sheath of aspect C1 whereinthe implant is adapted for disposition within or adjacent to an eye of apatient.

Embodiment C4 concerns the precursor sheath of aspect C1 wherein anamount of the therapeutic agent in a volumetric portion of the precursordrug core varies from an amount of the therapeutic agent in any otherequal volumetric portion of the precursor drug core by no greater thanabout 30%.

Embodiment C5 concerns the precursor sheath of aspect C1 wherein anamount of the therapeutic agent in a volumetric portion of the precursordrug core varies from an amount of the therapeutic agent in any otherequal volumetric portion of the precursor drug core by no greater thanabout 20%.

Embodiment C6 concerns the precursor sheath of aspect aspect C1 whereinan amount of the therapeutic agent in a volumetric portion of theprecursor drug core varies from an amount of the therapeutic agent inany other equal volumetric portion of the precursor drug core by nogreater than about 10%.

Embodiment C7 concerns the precursor sheath of aspect C1 wherein anamount of the therapeutic agent in a volumetric portion of the precursordrug core varies from an amount of the therapeutic agent in any otherequal volumetric portion of the precursor drug core by no greater thanabout 5%.

Embodiment C8 concerns the precursor sheath of aspect C1 wherein theamount of the agent in a first insert of the plurality of inserts issimilar to the amount of agent in any other insert of the plurality ofinserts.

Embodiment C9 concerns the precursor sheath of embodiment C8 wherein theamount of the agent in the first insert varies by no greater than about30% compared with the amount of agent in any other insert.

Embodiment C10 concerns the precursor sheath of embodiment C8 whereinthe amount of the agent in the first insert varies by no greater thanabout 20% compared with the amount of agent in any other insert.

Embodiment C11 concerns the precursor sheath of embodiment C8 whereinthe amount of the agent in the first insert varies by no greater thanabout 10% compared with the amount of agent in any other insert.

Embodiment C12 concerns the precursor sheath of embodiment C8 whereinthe amount of the agent in the first insert varies by no greater thanabout 5% compared with the amount of agent in any other insert.

Embodiment C13 concerns the precursor sheath of aspect C1 wherein theimplant comprises a punctal plug and each of the plurality of inserts isadapted for disposition within a, respective plurality thereof.

Embodiment C14 concerns the precursor sheath of embodiment C13 whereineach exposed surface of each drug insert divided therefrom is adapted torelease therapeutic quantities of the agent for a time period of atleast several days into tear fluid, when the insert is disposed within apunctal plug and the punctal plug is disposed within a punctum of apatient.

Embodiment C15 concerns the precursor sheath of aspect C1 wherein thedrug core comprises about 0.1 wt % to about 50 wt % of the agent.

Embodiment C16 concerns the precursor sheath of aspect C1 wherein thematrix comprises a non-biodegradable silicone or a polyurethane, orcombination thereof.

Embodiment C17 concerns the precursor sheath of aspect C1 wherein thesheath body comprises a polymer comprising at least one of polyimide,PMMA, PET, wherein the polymer is extruded or cast, or stainless steel,or titanium.

Embodiment C18 concerns the precursor sheath of aspect C1 wherein theagent comprises wherein the agent comprises a glaucoma medication, amuscarinic agent, a beta blocker, an alpha agonist, a carbonic anhydraseinhibitor, a prostaglandin or prostaglandin analog; an anti-inflammatoryagent; an anti-infective agent; a dry eye medication; or any combinationthereof.

Embodiment C19 concerns the precursor sheath of embodiment C18 whereinthe anti-inflammatory agent comprises a steroid, a soft steroid, or anNSAID and/or other compounds with analgesic properties.

Embodiment C20 concerns the precursor sheath of embodiment C18 whereinthe anti-infective agent comprises an antibiotic, an antiviral, or anantimycotic.

Embodiment C21 concerns the precursor sheath of embodiment C18 whereinthe dry eye medication comprises cyclosporine, antihistamines and mastcell stabilizers, olapatadine, a demulcent, or sodium hyaluronate.

Embodiment C22 concerns the precursor sheath of aspect C1 wherein theagent comprises latanoprost, and the amount of the agent in each of theplurality of drug inserts is about 10-50 μg.

Embodiment C23 concerns the precursor sheath of aspect C1 wherein thedrug insert comprises a release rate modifying material comprising aninert filler material, a salt, a surfactant, a dispersant, a secondpolymer, an oligomer, or a combination thereof.

Embodiment C24 concerns the precursor sheath of aspect C1 adapted fordivision by cutting with a blade or with a laser.

Embodiment C25 concerns the precursor sheath of aspect C1 wherein theagent is dissolved in the matrix.

Embodiment C26 concerns the precursor sheath of aspect C1 wherein theagent is dispersed as a plurality of solid or liquid inclusionsthroughout the matrix, the inclusions comprising, at a temperature ofless than about 25° C., droplets of the agent of no greater than about100 μm diameter when the agent is a liquid at less than about 25° C., orparticles of the agent of no greater than about 100 μm diameter when theagent is a solid at less than about 25° C.

Embodiment C27 concerns the precursor sheath of embodiment C26 whereinthe inclusions have an average diameter of less than about 20 μm.

Embodiment C28 concerns the precursor sheath of embodiment C27 wherein astandard deviation of diameters of the inclusions is less than about 8μm.

Embodiment C29 concerns the precursor sheath of embodiment C26 whereinthe inclusions have an average diameter of less than about 10 μm.

Embodiment C30 concerns the precursor sheath of embodiment C29 wherein astandard deviation of diameters of the inclusions is less than about 4μm.

Embodiment C31 concerns the precursor sheath of embodiment C26 wherein asize distribution of diameters of the plurality of inclusions ismonodisperse.

Embodiment C32 concerns the precursor sheath of aspect C1 wherein: a)the therapeutic agent is uniformly and homogeneously dispersedthroughout the matrix; or b) the therapeutic agent at least in partforms solid or liquid inclusions within the matrix.

The filled precursor sheath aspects and embodiments of aspect C1 andembodiments C2 through C32 can be combined in any manner, as long as thecombination is not internally inconsistent. For example, embodiment C6may be combined with any of embodiments C2 through C5. Thesecombinations are intended to provide the same concepts and meanings asmultiply-dependent claims have and also the concepts and meanings thatmultiply-dependent claims upon other multiply-dependent claims have, sothat any and all combinations of preceding and succeeding subject matterare included for this aspect and embodiment set.

Aspect D1 concerns an implant body for disposition in or adjacent to abody cavity, tissue, duct, or fluid of a patient, the implant bodycomprising a channel therein adapted to receive a drug insert such thatan exposed surface of the insert will be exposed to the body cavity,tissue, duct or fluid when the insert is disposed within the implant andwhen the implant is disposed in or adjacent to the body cavity, tissue,duct or fluid, the drug insert comprising a sheath body that issubstantially impermeable to the agent, the sheath body containing adrug core comprising a therapeutic agent and a matrix comprising apolymer, wherein an amount of the therapeutic agent in a volumetricportion of the precursor drug core is similar to an amount of thetherapeutic agent in any other equal volumetric portion of the precursordrug core.

Embodiment D2 concerns an implant body of aspect D1 wherein the implantis adapted for disposition within or adjacent to an eye of a patient.

Embodiment D3 concerns the implant body of Aspect D1, wherein the amountof the therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 30%.

Embodiment D4 concerns the implant body of Aspect D1, wherein the amountof the therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 20%.

Embodiment D5 concerns the implant body of Aspect D1, wherein the amountof the therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 10%.

Embodiment D6 concerns the implant body of aspect D1, wherein the amountof the therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 5%.

Embodiment D7 concerns the implant of aspect D1, wherein the exposedsurface is capable of releasing the therapeutic quantities into at leastone of a sclera, a cornea or a vitreous when disposed in or adjacent tothe eye of the patient.

Embodiment D8 concerns the implant of aspect D1 comprising a punctalplug adapted for disposition within a punctum of a patient for releaseof the agent into tear liquid.

Embodiment D9 concerns the implant of aspect D1, wherein the therapeuticagent is soluble in the matrix.

Embodiment D10 concerns the implant of aspect D1 wherein the therapeuticagent forms inclusions within the matrix but is sufficiently soluble inor transportable through the matrix such that when the implant isdisposed adjacent to an eye, the exposed surface is capable of releasingtherapeutic quantities of the agent to the tear liquid for a period oftime when the implant is disposed in or adjacent to the eye.

Embodiment D11 concerns the implant of aspect D1 wherein a rate ofrelease of the agent is determined in part by a concentration of theagent that dissolves in the matrix.

Embodiment D12 concerns the implant of aspect D1 wherein the matrixcomprises a crosslinked water insoluble solid material that contains theinclusions.

Embodiment D13 concerns the implant of embodiment D12 wherein thecrosslinked water insoluble solid material comprises a silicone or apolyurethane

Embodiment D14 concerns the implant of aspect D1 wherein the matrixfurther comprises an effective amount of a release rate varyingmaterial, the release rate varying material comprising at least one of acrosslinker, an inert filler material, a surfactant, a dispersant, asecond polymer, or an oligomer, or any combination thereof.

Embodiment D15 concerns the implant of aspect D1 wherein the drug corecomprises from about 5% to about 50% of the therapeutic agent.

Embodiment D16 concerns the implant of embodiment D10 wherein theinclusions of agent are in physical form liquid or solid.

Embodiment D17 concerns the implant of aspect D1 wherein the sheath bodycomprises a polymer comprising at least one of polyimide, PMMA, PET,wherein the polymer is extruded or case, or stainless steel, ortitanium.

Embodiment D18 concerns the implant of aspect D1 wherein the implantbody comprises at least one of a silicone or a hydrogel.

Embodiment D19 concerns the implant of aspect D1 wherein the agent isdispersed as a plurality of solid or liquid inclusions throughout thematrix, the inclusions comprising, at a temperature of less than about25° C., droplets of the agent of no greater than about 200 μm diameterwhen the agent is a liquid at less than about 25° C., or particles ofthe agent of no greater than about 200 μm diameter when the agent is asolid at less than about 25° C.

Embodiment D20 concerns the implant of embodiment D19 wherein theinclusions have an average diameter of less than about 20 μm.

Embodiment D21 concerns the implant of embodiment D20 wherein a standarddeviation of diameters of the inclusions is less than about 8 μm.

Embodiment D22 concerns the implant of embodiment D19 wherein theinclusions have an average diameter of less than about 15 μm.

Embodiment D23 concerns the implant of embodiment D22 wherein a standarddeviation of diameters of the inclusions is less than about 6 μm.

Embodiment D24 concerns the implant of embodiment D19 wherein theinclusions have an average diameter of less than about 10 μm.

Embodiment D25 concerns the implant of embodiment D24 wherein a standarddeviation of diameters of the inclusions is less than about 4 μm.

Embodiment D26 concerns the implant of embodiment D19 wherein a sizedistribution of diameters of the plurality of inclusions ismonodisperse.

Embodiment D27 concerns the implant of embodiment D19 wherein theinclusions comprise a cross-sectional size within a range from about 0.1μm to about 50 μm.

Embodiment D28 concerns the implant of embodiment D19 wherein the agentforms inclusions in the matrix that are in a liquid physical state atless than about 25° C.

Embodiment D29 concerns the implant of embodiment D19 wherein the agentforms inclusions in the matrix that are in a solid physical state atless than about 25° C.

Embodiment D30 concerns the implant of aspect D1 wherein: a) thetherapeutic agent is uniformly and homogeneously dispersed throughoutthe matrix; or b) the therapeutic agent at least in part forms solid orliquid inclusions within the matrix.

The implant body aspects and embodiments of aspect D1 and embodiments D2through D30 can be combined in any manner, as long as the combination isnot internally inconsistent. For example, embodiment D6 may be combinedwith any of embodiments D2 through D5. These combinations are intendedto provide the same concepts and meanings as multiply-dependent claimshave and also the concepts and meanings that multiply-dependent claimsupon other multiply-dependent claims have, so that any and allcombinations of preceding and succeeding subject matter are included forthis aspect and embodiment set.

Aspect E1 concerns a method of manufacturing a drug insert for animplant body adapted for disposition within or adjacent to a bodycavity, tissue, duct, or fluid of a patient, the insert comprising adrug core and a sheath body partially covering the drug core, the drugcore comprising a therapeutic agent and a matrix the matrix comprising apolymer, the sheath body being disposed over a portion of the drug coreto inhibit release of the agent from said portion and so as to define atleast one exposed surface of the drug core adapted to release the agentwhen the implant is inserted into the patient, the method comprisinginjecting into the sheath body, at a temperature of less than about 25°C., a mixture comprising a matrix precursor and the therapeutic agentsuch that the sheath body is substantially filled therewith; then,curing the mixture within the sheath body to form within the sheath bodythe drug core wherein an amount of the therapeutic agent in a volumetricportion of the drug core is similar to an amount of the therapeuticagent in any other equal volumetric portion of the drug core.

Aspect E2 concerns a method of manufacturing a drug insert for animplant body adapted for disposition within or adjacent to a bodycavity, tissue, duct, or fluid of a patient, the method comprisinginjecting into a precursor sheath body, at a temperature of less thanabout 25° C., a mixture comprising a therapeutic agent and a precursormatrix such that the precursor sheath is substantially filled therewith,the precursor sheath body being substantially impermeable to the agent,curing the mixture in the precursor sheath body to provide a cured,filled precursor sheath body containing a precursor drug core; anddividing the cured filled precursor sheath to form a plurality of druginserts, each drug insert being adapted to fit within a respectiveimplant body, wherein each drug insert comprises a drug core and asheath body, the sheath body being disposed over a portion of the drugcore to inhibit release of the agent from said portion and so as todefine at least one exposed surface of the drug core adapted to releasethe agent when the insert is disposed with an implant and the implant isinserted into the patient, and wherein an amount of the therapeuticagent in a volumetric portion of the drug core is similar to an amountof the therapeutic agent in any other equal volumetric portion of thedrug core.

Embodiment E3 concerns a method of manufacturing a drug insert of aspectE2 wherein each of the plurality of drug inserts is of substantially thesame length, and wherein an amount of the agent in a first insert of theplurality is similar to the amount of agent in any other insert of theplurality.

Embodiment E4 concerns the method of manufacturing a drug insertaccording to aspect E1, aspect E2, or embodiment E3 wherein the implantis adapted for disposition in or adjacent to an eye of a patient.

Embodiment E5 concerns the method of aspect E1 or E2 wherein the amountof the therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 30%.

Embodiment E6 concerns the method of aspect E1 or E2 wherein the amountof the therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 20%.

Embodiment E7 concerns the method of aspect E1 or E2 wherein the amountof the therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 10%.

Embodiment E8 concerns the method of aspect E1 or E2 wherein the amountof the therapeutic agent in a volumetric portion of the drug core variesfrom the amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 5%.

Embodiment E9 concerns the method of aspect E2 wherein the amount of theagent in each of the plurality of inserts varies by no greater thanabout 30% therebetween.

Embodiment E10 concerns the method of aspect E2 wherein the amount ofthe agent in each of the plurality of inserts varies by no greater thanabout 20% therebetween.

Embodiment E11 concerns the method of aspect E2 wherein the amount ofthe agent in each of the plurality of inserts varies by no greater thanabout 10% therebetween.

Embodiment E12 concerns the method of aspect E2 wherein the amount ofthe agent in each of the plurality of inserts varies by no greater thanabout 5% therebetween.

Embodiment E13 concerns the method of aspect E2 wherein dividing theprecursor insert comprises cutting the precursor insert with a blade orwith a laser.

Embodiment E14 concerns the method of aspect E1 or E2 wherein theimplant comprises a punctal plug adapted to be disposed within thepunctum of the patient.

Embodiment E15 concerns the method of embodiment E14 wherein the exposedsurface is adapted to release therapeutic quantities of the agent for atime period of at least several days into tear fluid when the insert isdisposed in the punctal plug and the punctal plug is disposed within apunctum of a patient.

Embodiment E16 concerns the method of aspect E1 or E2 wherein themixture further comprises a solvent in which the matrix precursor andthe agent are soluble, and wherein curing comprises at least partialremoval of the solvent following injection into the sheath body orprecursor sheath body respectively.

Embodiment E17 concerns the method of embodiment E16 wherein curingcomprises heating, vacuum treatment, or both.

Embodiment E18 concerns the method of embodiment E16 wherein the solventcomprises a hydrocarbon, an ester, a halocarbon, an alcohol, an amide,or a combination thereof.

Embodiment E19 concerns the method of embodiment E16 wherein the solventcomprises a halocarbon and the agent comprises cyclosporine.

Embodiment E20 concerns the method of aspect E1 or E2 wherein curing themixture comprises heating the mixture to a temperature, at a relativehumidity, for a period of time.

Embodiment E21 concerns the method of embodiment E20 wherein thetemperature comprises a range from about 20° C. to about 100° C., therelative humidity comprises a range from about 40% to about 100%, andthe period of time comprises a range from about 1 minute to about 48hours.

Embodiment E22 concerns the method of embodiment E21 wherein thetemperature is at least about 40° C., the relative humidity is at leastabout 80%, or both.

Embodiment E23 concerns the method of aspect E1 or E2 wherein curingcomprises a step of polymerization or cross-linking, or both, of thematrix precursor.

Embodiment E24 concerns the method of embodiment E23 comprisingpolymerization or cross-linking, or both, in the presence of a catalyst.

Embodiment E25 concerns the method of embodiment E24 wherein thecatalyst comprises a tin compound or a platinum compound.

Embodiment E26 concerns the method of embodiment E24 wherein thecatalyst comprises at least one of a platinum with vinyl hydride systemor a tin with alkoxy system.

Embodiment E27 concerns the method of aspect E1 or E2 wherein themixture is prepared by a method comprising sonication.

Embodiment E28 concerns the method of aspect E1 or E2 wherein injectingcomprises injecting under a pressure of at least about 40 psi.

Embodiment E29 concerns the method of aspect E1 or E2 wherein thetemperature comprises a temperature of about −50° C. to about 25° C.

Embodiment E30 concerns the method of aspect E1 or E2 wherein thetemperature comprises a temperature of about −20° C. to about 0° C.

Embodiment E31 concerns the method of aspect E1 or E2 wherein themixture is injected such that the sheath body or precursor sheath body,respectively, is filled at a rate of no greater than about 0.5 cm/sec.

Embodiment E32 concerns the method of aspect E1 or E2 wherein each druginsert is sealed at one end thereof, a second end providing the exposedsurface.

Embodiment E33 concerns the method of embodiment E32 wherein each druginsert is sealed at one end thereof with a UV-curable adhesive, acyanoacrylate, an epoxy, by pinching, with a heat weld, or with a cap.

Embodiment E34 concerns the method of embodiment E33 further comprisesirradiating the drug insert with a UV-curable adhesive with UV light.

Embodiment E35 concerns the method of embodiment E33 further comprising,after sealing one end thereof, inserting each drug insert into a channelof an implant body adapted to receive the insert therein.

Embodiment E36 concerns the method of aspect E1 or E2 wherein the insertcomprises about 0.1 wt % to about 50 wt % of the agent.

Embodiment E37 concerns the method of aspect E1 or E2 wherein the matrixcomprises a non-biodegradable silicone or a polyurethane.

Embodiment E38 concerns the method of aspect E1 or E2 wherein the sheathor precursor sheath comprises at least one of polyimide, PMMA, PET,stainless steel, or titanium.

Embodiment E39 concerns the method of aspect E1 or E2 wherein the agentcomprises a glaucoma medication, a muscarinic agent, a beta blocker, analpha agonist, a carbonic anhydrase inhibitor, or a prostaglandin orprostaglandin analog; an antiinflammatory agent; an anti-infectiveagent; a dry eye medication; or any combination thereof.

Embodiment E40 concerns the method of embodiment E39 wherein theanti-inflammatory agent comprises a steroid, a soft steroid, or an NSAIDand/or any other compound with analgesic properties.

Embodiment E41 concerns the method of embodiment E39 wherein theanti-infective agent comprises an antibiotic, an antiviral, or anantimicotic.

Embodiment E42 concerns the method of embodiment E39 wherein the dry eyemedication comprises cyclosporine, olapatadine, delmulcents, or sodiumhyaluronate.

Embodiment E43 concerns the method of aspect E1 or E2 wherein the agentcomprises latanoprost, the matrix comprises silicone or polyurethane,and the amount of the agent in each of the plurality of drug inserts isabout 10-50 μg.

Embodiment E44 concerns the method of aspect E1 or E2 wherein the agentcomprises cyclosporine, the matrix comprises silicone or polyurethane,and a relative amount of the agent in each of the plurality of druginserts is ranges from about 1% to about 50% of the core.

Embodiment E45 concerns the method of aspect E1 or E2 wherein the druginsert comprises a release rate modifying material comprising an inertfiller material, a salt, a surfactant, a dispersant, a second polymer,an oligomer, or a combination thereof.

Embodiment E46 concerns the method of aspect E1 or E2 wherein the drugcore is substantially cylindrical in form, having an axis, wherein asurface of the drug core is not covered by the sheath is disposed on oneend on the cylindrical form and is the drug core covered by the sheathis disposed on a remainder of the surface of the cylindrical form.

Embodiment E47 concerns the method of aspect E1 or E2 wherein the agentis dissolved in the matrix.

Embodiment E48 concerns the method of embodiment E47 wherein the agentcomprises cyclosporine and the matrix comprises polyurethane.

Embodiment E49 concerns the method of aspect E1 or E2 wherein the agentis dispersed as a plurality of solid or liquid inclusions within thematrix, the inclusions comprising, at a temperature of less than about25° C., droplets of the agent of no greater than about 200 μm diameterwhen the agent is a liquid at less than about 25° C., or particles ofthe agent of no greater than about 200 μm diameter when the agent is asolid at less than about 25° C.

Embodiment E50 concerns the method of embodiment E49 wherein theinclusions have an average diameter of less than about 20 μm.

Embodiment E51 concerns the method of embodiment E50 wherein a standarddeviation of diameters of the inclusions is less than about 8 μm.

Embodiment E52 concerns the method of embodiment E49 wherein theinclusions have an average diameter of less than about 15 μm.

Embodiment E53 concerns the method of embodiment E52 wherein a standarddeviation of diameters of the inclusions is less than about 6 μm.

Embodiment E54 concerns the method of embodiment E49 wherein theinclusions wherein the inclusions have an average diameter of less thanabout 10 μm.

Embodiment E55 concerns the method of embodiment E54 wherein a standarddeviation of diameters of the inclusions is less than about 4 μm.

Embodiment E56 concerns the method of embodiment E49 wherein adistribution of diameters of the inclusions is a monodispersedistribution.

Embodiment E57 concerns the method of embodiment E49 wherein the mixtureis prepared by a process comprising sonication.

Embodiment E58 concerns the method of embodiment E49 wherein theinclusions comprise a cross-sectional size within a range from about 0.1μm to about 50 μm.

Embodiment E59 concerns the method of embodiment E49 wherein the agentforms inclusions within the matrix that are in physical state a liquidat less than about 25° C.

Embodiment E60 concerns the method of embodiment E59 whereinsubstantially all the inclusions are droplets of the agent of less thanabout 50 μm in diameter within the matrix.

Embodiment E61 concerns the method of embodiment E59 wherein an averagedroplet diameter within the matrix is about 5-50 μm.

Embodiment E62 concerns the method of embodiment E59 wherein the agentis latanoprost.

Embodiment E63 concerns the method of embodiment E49 wherein thephysical state of the agent is a solid at less than about 25° C.

Embodiment E64 concerns the method of embodiment E63 wherein the agentforms inclusions in the matrix and the physical state of the inclusionsis a solid at less than about 25° C.

Embodiment E65 concerns the method of embodiment E63 whereinsubstantially all the inclusions are particles of the agent of less thanabout 50 μm in diameter within the matrix.

Embodiment E66 concerns the method of embodiment E63 wherein an averageparticle diameter within the matrix is about 5-50 μm.

Embodiment E67 concerns the method of embodiment E63 wherein the agentis bimatoprost, olopatadine, or cyclosporine.

Embodiment E68 concerns the method of aspect E1 or E2 wherein each druginsert comprises two or more therapeutic agents.

Embodiment E69 concerns the method of aspect E1 or E2 wherein each drugcore comprises first and second drug cores.

Embodiment E70 concerns the method of embodiment E69 wherein the firstand second drug cores are positioned side by side and together form acylinder which is the drug core within the sheath body.

Embodiment E71 concerns the method of embodiment E69 wherein the drugcore comprises two drug cores, a first drug core comprising a firstagent and a first matrix, and a second drug core comprising a secondagent and a second matrix, wherein the first agent and the second agentare different, and wherein the first matrix and the second matrix areeither the same or differ from each other, the implant body comprisingan aperture adapted to receive the drug insert comprising the first andthe second drug cores, the method further comprising disposing the drugcores within the insert prior to disposing the insert within theaperture of the implant body.

Embodiment E72 concerns the method of embodiment E71 wherein the firstmatrix and the second matrix differ from each other with respect to atleast one of a composition, an exposed surface area, a surfactant, acrosslinker, an additive, a matrix material, a formulation, or astability.

Embodiment E73 concerns the method of embodiment E71 wherein the firstdrug core and the second drug core are disposed within the sheath suchthat the first drug core has a surface exposed directly to tear liquidand the second drug core has a surface exposed the first drug core.

Embodiment E74 concerns the method of embodiment E71 wherein the firstdrug core and the second drug core are disposed side by side within thesheath.

Embodiment E75 concerns the method of embodiment E71 wherein the firstdrug core and the second drug core are each cylindrical in shape anddisposed with the drug core, the first drug core being positioned near aproximal end of an aperture in the implant body adapted to receive thedrug core and the second drug core being positioned near a distal end ofthe aperture.

Embodiment E76 concerns the method of embodiment E71 wherein the firstdrug core and the second drug core are each cylindrical in shape and arepositioned concentrically within an aperture of the implant body adaptedto receive the drug cores, the first drug core having a first centralopening and the second drug core being configured to fit within thefirst central opening of the first drug core.

Embodiment E77 concerns the method of embodiment E71 wherein the firstand second drug cores are concentrically positioned within the aperture,the first drug core having a first central opening exposing a firstinner surface and the second drug core having a second central openingexposing a second inner surface, the second drug core being configuredto fit within the first central opening of the first drug core, andwherein the aperture extends from a proximal end to a distal end of theimplantable body adapted to allow a tear or tear film fluid to passthrough the aperture and contact the first and second inner surfaces ofthe first and second central openings and release the first and secondtherapeutic agents into a canaliculus.

Embodiment E78 concerns the method of embodiment E71 wherein the insertis adapted such that when it is implanted the first therapeutic agentreleases at therapeutic levels throughout a first time period and thesecond therapeutic agent releases at therapeutic levels throughout asecond time period.

Embodiment E79 concerns the method of embodiment E71 wherein the firsttherapeutic agent releases at therapeutic levels throughout a first timeperiod and the second therapeutic agent releases at therapeutic levelsthroughout a second time period.

Embodiment E80 concerns the method of embodiment E79 wherein the firsttime period and the second time period are between one week and fiveyears.

Embodiment E81 concerns the method of embodiment E79 wherein the firsttime period and the second time period are substantially the same.

Embodiment E82 concerns the method of embodiment E79 wherein the firsttime period and the second timer period are different.

Embodiment E83 concerns the method of embodiment E71 further comprisingdisposing a head coupled to the implant body covering the aperture, thehead being permeable to the first and second therapeutic agents.

Embodiment E84 concerns the method of embodiment E71, wherein thetherapeutic levels are drop administered quantities or less.

Embodiment E85 concerns the method of embodiment E71, wherein thetherapeutic levels are less than 10% of drop administered quantities.

Embodiment E86 concerns the method of embodiment E71, further comprisingdisposing a medication-impregnated porous material within the firstmatrix, the second matrix, or both, the medication-impregnated porousmaterial being adapted such that tear liquid releases the first agent,the second agent, or both, therefrom at therapeutic levels over asustained period when a drug core-containing implant is disposed withina punctum, wherein the medication-impregnated porous material is a gelmaterial that can swell from a first diameter to a second diameter.

Embodiment E87 concerns the method of embodiment E86 wherein in whichthe second diameter is about 50% greater than the first diameter.

Embodiment E88 concerns the method of embodiment E86 wherein themedication-impregnated porous material is a HEMA hydrophilic polymer.

Embodiment E89 concerns the method of embodiment E71 wherein the implantbody comprises a central bore that extends from a proximal end to adistal end of the implant body adapted to allow a tear liquid to passthrough the implant body and release the first and second therapeuticagents into a canaliculus.

Embodiment E90 concerns the method of embodiment E71 wherein the firstagent provides a first effect and a side effect to the patient, and thesecond agent provides a second effect that mitigates or counters theside effect of the first agent.

Embodiment E91 concerns the method of aspect E1 or E2 wherein the matrixcomprises a polyurethane polymer or copolymer.

Embodiment E92 concerns the method of embodiment E91 wherein thepolyurethane polymer or copolymer comprises an aliphatic polyurethane,an aromatic polyurethane, a polyurethane hydrogel-forming material, ahydrophilic polyurethane, or a combination thereof.

Embodiment E93 concerns the method of embodiment E91 wherein thepolyurethane polymer or copolymer comprises a hydrogel adapted to swellwhen contacted with an aqueous medium and the sheath is adapted to be ofsufficient elasticity to expand in response thereto.

Embodiment E94 concerns the method of embodiment E93 wherein theswelling is adapted to retain the plug within the punctal canal.

Embodiment E95 concerns the method of embodiment E91 wherein thetherapeutic agent comprises cyclosporine or olopatadine, a prodrug or aderivative of cyclosporine or olopatadine or any combination thereof.

Embodiment E96 concerns the method of embodiment E95 wherein a weightratio of the cyclosporine or the olopatadine or the cyclosporine prodrugor derivative, or the olopatadine prodrug or derivative, or thecombination thereof, to the polyurethane polymer or copolymer is about 1wt % to about 70 wt %.

Embodiment E97 concerns the method of embodiment E95 wherein thepolyurethane polymer or copolymer, and a quantity or a concentration ofthe cyclosporine or olopatadine, or the prodrug or derivative ofcyclosporine or olopatadine, or combination thereof, therein, isselected to provide a release profile of the agent into tear liquid ofthe patient.

Embodiment E98 concerns the method of embodiment E91 wherein the drugcore further comprises a second therapeutic agent.

Embodiment E99 concerns the method of embodiment E91, comprising formingthe mixture by melting and mixing the polyurethane polymer or copolymerand the therapeutic agent.

Embodiment E100 concerns the method of embodiment E99 wherein thetherapeutic agent is in molten form in the mixture.

Embodiment E101 concerns the method of embodiment E99 wherein thetherapeutic agent is in solid form in the mixture.

Embodiment E102 concerns the drug insert made by a method of aspect E1or E2.

Embodiment E103 concerns the method of aspect E1 or E2, wherein thetemperature comprises a temperature of less than about 25° C.

Embodiment E104 concerns the method of aspect E1 or E2, wherein thetemperature comprises a temperature of less than about 15° C.

Embodiment E105 concerns the method of aspect E1 or E2, wherein thetemperature comprises a temperature of less than about 10° C.

Embodiment E106 concerns the method of aspect E1 or E2, wherein thetemperature comprises a temperature of less than about 5° C.

Embodiment E107 concerns the method of aspect E1 or E2 wherein: a) thetherapeutic agent is uniformly and homogeneously dispersed throughoutthe matrix; or b) the therapeutic agent at least in part forms solid orliquid inclusions within the matrix.

The method of manufacturing aspects and embodiments of aspects E1 and E2and embodiments E3 through E107 can be combined in any manner, as longas the combination is not internally inconsistent. For example,embodiment E6 may be combined with any of embodiments E3 through E5.These combinations are intended to provide the same concepts andmeanings as multiply-dependent claims have and also the concepts andmeanings that multiply-dependent claims upon other multiply-dependentclaims have, so that any and all combinations of preceding andsucceeding subject matter are included for this aspect and embodimentset.

Aspect F1 concerns a method of treating a malcondition in a patient inneed thereof, comprising disposing in the patient an implant comprisinga drug insert of any one of aspect A1 and embodiments A2-A78 or a drugcore of any one of aspect B1 and embodiments B2-B28, or a drug coreobtained by division of a filled precursor sheath of any one of aspectC1 and embodiments C2-C32, or a drug implant of any one of aspect D1 andembodiments D2-D30, or a drug insert of embodiment E102, wherein thetherapeutic agent is adapted to treat the malcondition, in or adjacentto an eye of the patient such that the drug is released into a bodytissue or fluid.

Embodiment F2 concerns the method of aspect F1 wherein the malconditioncomprises glaucoma, and the agent is a prostaglandin analog.

Embodiment F3 concerns the method of embodiment F2 wherein the matrixcomprises a non-biodegradable silicone or polyurethane polymer.

Embodiment F4 concerns the method of embodiment F2 wherein theprostaglandin analog is latanoprost.

Embodiment F5 concerns the method of aspect F1 wherein the malconditioncomprises dry eye or eye inflammation and the agent is cyclosporine orolopatadine or a prodrug or derivative of cyclosporine or olopatadine.

Embodiment F6 concerns the method of embodiment F5 wherein the matrixcomprises polyurethane.

Aspect G1 concerns a drug insert adapted for disposition within alacrimal implant for providing sustained release of latanoprost to aneye of a patient in need of treatment of glaucoma, the drug insertcomprising a drug core and a sheath body partially covering the drugcore, the drug core comprising latanoprost and a matrix, the matrixcomprising a silicone polymer, the sheath body being disposed over aportion of the drug core to inhibit release of the latanoprost from thatportion and so as to define at least one exposed surface of the drugcore not covered by the sheath body thereby being adapted to release thelatanoprost to the eye, wherein an amount of the latanoprost in avolumetric portion of the drug core is similar to an amount of thelatanoprost in any other equal volumetric portion of the drug core.

Embodiment G2 concerns the drug insert of aspect G1 wherein the amountof the latanoprost in a volumetric portion of the drug core varies fromthe amount of the latanoprost in any other equal volumetric portion ofthe drug core by no greater than about 30%.

Embodiment G3 concerns the drug insert of aspect G1 wherein the amountof the latanoprost in a volumetric portion of the drug core varies fromthe amount of the latanoprost in any other equal volumetric portion ofthe drug core by no greater than about 20%.

Embodiment G4 concerns the drug insert of aspect G1 wherein the amountof the latanoprost in a volumetric portion of the drug core varies fromthe amount of the latanoprost in any other equal volumetric portion ofthe drug core by no greater than about 10%.

Embodiment G5 concerns the drug insert of aspect G1 wherein the amountof the latanoprost in a volumetric portion of the drug core varies fromthe amount of the latanoprost in any other equal volumetric portion ofthe drug core by no greater than about 5%.

Embodiment G6 concerns the drug insert of aspect Gl, wherein thelatanoprost is dispersed within the silicone as droplets thereof.

The drug insert aspects and embodiments of aspect G1 and embodiments G2through G6 can be combined in any manner, as long as the combination isnot internally inconsistent. For example, embodiment G6 may be combinedwith any of embodiments G2 through G5. These combinations are intendedto provide the same concepts and meanings as multiply-dependent claimshave and also the concepts and meanings that multiply-dependent claimsupon other multiply-dependent claims have, so that any and allcombinations of preceding and succeeding subject matter are included foran aspect and embodiment set.

Aspect H1 concerns a drug insert adapted for disposition within anpunctal plug for providing sustained release of a cyclosporine to theeye for treatment of dry eye or inflammation, the insert comprising adrug core and a sheath body partially covering the core, the drug corecomprising the cyclosporine and a matrix, the matrix comprising apolyurethane polymer, the sheath body being disposed over a portion ofthe core to inhibit release of the cyclosporine from said portion and soas to define at least one exposed surface of the drug core not coveredby the sheath body being adapted to release the cyclosporine to the eye,wherein an amount of the cyclosporine in a volumetric portion of thedrug core is similar to an amount of the cyclosporine in any other equalvolumetric portion of the drug core.

Embodiment H2 concerns the drug insert of aspect H1 wherein the amountof the cyclosporine in a volumetric portion of the drug core varies fromthe amount of the cyclosporine in any other equal volumetric portion ofthe drug core by no greater than about 30%.

Embodiment H3 concerns the drug insert of aspect H1 wherein the amountof the cyclosporine in a volumetric portion of the drug core varies fromthe amount of the cyclosporine in any other equal volumetric portion ofthe drug core by no greater than about 20%.

Embodiment H4 concerns the drug insert of aspect H1 wherein the amountof the cyclosporine in a volumetric portion of the drug core varies fromthe amount of the cyclosporine in any other equal volumetric portion ofthe drug core by no greater than about 10%.

Embodiment H5 concerns the drug insert of aspect H1 wherein the amountof the cyclosporine in a volumetric portion of the drug core varies fromthe amount of the cyclosporine in any other equal volumetric portion ofthe drug core by no greater than about 5%.

Embodiment H6 concerns the drug insert of aspect H1, wherein thecyclosporine is dissolved within the polyurethane.

The drug insert aspects and embodiments of aspect Hi and embodiments H2through H6 can be combined in any manner, as long as the combination isnot internally inconsistent. For example, embodiment H6 may be combinedwith any of embodiments H2 through H5. These combinations are intendedto provide the same concepts and meanings as multiply-dependent claimshave and also the concepts and meanings that multiply-dependent claimsupon other multiply-dependent claims have, so that any and allcombinations of preceding and succeeding subject matter are included foran aspect and embodiment set.

Further aspects and embodiments include the following.

The drug insert of any one of aspect A1 and embodiments A1-A78, or thedrug core of any one of aspect B1 and embodiments B2-B28, or the drugcore obtained by division of a filled precursor sheath of any one ofaspects C1 and embodiments C2-C32, or the drug implant of any one ofaspect D1 and embodiments D2-D30, or the drug insert of embodiment E102,adapted for providing sustained release of a therapeutic agent to theeye or surrounding tissues, or systemically, or any combination thereof.

A drug core of any of aspect A1 and embodiments A2-A78 which has beenformed into a shape of an implant body for disposition in or adjacent toa body cavity, tissue, duct, or fluid of a patient.

Another aspect of the invention concerns the use of a drug insert of anyone of aspect A1 and embodiments A2-A78, or a drug core of any one ofaspect Bi or embodiments B2-B28, or a drug core obtained by division ofa filled precursor sheath of any one of aspect C1 or embodiments C2-C32,or a drug implant of any one of aspect D1 or embodiments D2-D30, or adrug insert of E102, in the manufacture of an implant adapted fortreatment of a malcondition in a patient in need thereof.

Another aspect of the invention concerns an implant comprising a polymerand a therapeutic agent disposed therein, wherein an amount of thetherapeutic agent in a volumetric portion of the implant is similar toan amount of the therapeutic agent in any other equal volumetric portionof the implant.

A further aspect of the invention concerns a method of manufacturing animplant comprising a polymer and a therapeutic agent disposed therein,wherein an amount of the therapeutic agent in a volumetric portion ofthe implant is similar to an amount of the therapeutic agent in anyother equal volumetric portion of the implant, in which the methodcomprises injecting a mixture comprising a polymer and a therapeuticagent into a mold, the method comprising injecting said mixture at atemperature less than about 25° C.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows a top cross sectional view of a sustained release implantto treat an optical defect of an eye, according to an embodiment of thepresent invention.

FIG. 1B shows a side cross sectional view of the sustained releaseimplant of FIG. 1A.

FIG. 1C shows a perspective view of a sustained release implant with acoil retention structure, according to an embodiment of the presentinvention.

FIG. 1D shows a perspective view of a sustained release implant with aretention structure comprising struts, according to an embodiment of thepresent invention.

FIG. 1E shows a perspective view of a sustained release implant with acage retention structure, according to an embodiment of the presentinvention.

FIG. 1F shows a perspective view of a sustained release implantcomprising a core and sheath, according to an embodiment of the presentinvention.

FIG. 1G schematically illustrates a sustained release implant comprisinga flow restricting retention element, a core and a sheath, according toan embodiment of the present invention.

FIG. 2A shows a cross sectional view of a sustained release implant withcore comprising an enlarged exposed surface area, according to anembodiment of the present invention.

FIG. 2B shows a cross sectional view of a sustained release implant witha core comprising an enlarged exposed surface area, according to anembodiment of the present invention.

FIGS. 2C and 2D show perspective view and cross sectional views,respectively, of a sustained release implant with a core comprising areduced exposed surface area, according to an embodiment of the presentinvention.

FIG. 2E shows a cross sectional view of a sustained release implant witha core comprising an enlarged exposed surface area with an indentationand castellation, according to an embodiment of the present invention.

FIG. 2F shows a perspective view of a sustained release implantcomprising a core with folds, according to an embodiment of the presentinvention.

FIG. 2G shows a perspective view of a sustained release implant with acore comprising a channel with an internal surface, according to anembodiment of the present invention.

FIG. 2H shows a perspective view of a sustained release implant with acore comprising porous channels to increase drug migration, according toan embodiment of the invention.

FIG. 2I shows a perspective view of a sustained release implant with aconvex exposed drug core surface, according to an embodiment of thepresent invention.

FIG. 2J shows a side view of a sustained release implant with a corecomprising an exposed surface area with several soft brush-like membersextending therefrom, according to an embodiment of the presentinvention.

FIG. 2K shows a side view of a sustained release implant with a drugcore comprising a convex exposed surface and a retention structure,according to an embodiment of the present invention.

FIG. 2L shows a side view of a sustained release implant with a drugcore comprising a concave indented surface to increase exposed surfacearea of the core, according to an embodiment of the present invention.

FIG. 2M shows a side view of a sustained release implant with a drugcore comprising a concave surface with a channel formed therein toincrease an exposed surface area of the core, according to an embodimentof the present invention.

FIGS. 3A and 3B show an implant comprising a silicone body, a drug coreand retention structures, according to embodiments of the presentinvention.

FIG. 3C shows insertion of the implant as in FIG. 3A into an uppercanaliculus of an eye.

FIG. 3D shows an implant as in FIG. 3A in an expanded profileconfiguration following implantation in the canaliculus of the eye.

FIG. 4A shows a drug core insert suitable for use with an implant,according to embodiments of the present invention.

FIG. 4B shows an of implant suitable for use with a drug core insert,according to embodiments of the present invention.

FIG. 4C shows an annular drug core insert suitable for use with animplant for systemic delivery of a therapeutic agent, according toembodiments of the present invention.

FIG. 4D shows an of implant suitable for use with a drug core insert asin FIG. 4C.

FIGS. 4E and 4F show a side cross-sectional view and an end view,respectively, of a drug core inserts with two drug cores, according toembodiments of the present invention.

FIGS. 5A to 5C schematically illustrate replacement of a drug core and asheath body, according to an embodiment of the present invention.

FIGS. 5D and 5E show an implant comprising a filament that extends froma drug core insert for removal the drug core insert from the implant,according to embodiments of the present invention.

FIG. 5F shows an implant comprising a filament that extends along a drugcore insert bonded to a distal end of the drug core insert for removalof the drug core insert from a body of the implant, according toembodiments of the present invention.

FIG. 6A shows a method of manufacturing a punctal plug, according toembodiments of the present invention.

FIG. 6B shows a method of manufacturing a hydrogel rod in accordancewith the method of FIG. 6A.

FIG. 6C shows a method of molding a silicone plug in accordance with themethod of FIG. 6A.

FIG. 6D shows a method of assembling the punctal plug component inaccordance with the method of in FIG. 6A.

FIG. 6E shows a method of manufacturing a drug core insert, inaccordance with the method of in FIG. 6A.

FIG. 6F shows method 690 of final assembly in accordance with method 600of FIG. 6A.

FIGS. 7A and 7B show elution data of latanoprost at day 1 and day 14,respectively, for the three core diameters of 0.006, 0.012 and 0.025inches and three Latanoprost concentrations of approximately 5%, 11% and18%, according to embodiments of the present invention.

FIG. 7C shows elution data for Latanoprost from 0.32 mm diameter, 0.95mm long drug cores with concentrations of 5, 10 and 20% and drug weightsof 3.5, 7 and 14 μg, respectively, according to embodiments of thepresent invention.

FIGS. 7D and 7E show dependence of the rate of elution on exposedsurface area of the drug core for the three core diameters and the threeconcentrations as in FIGS. 7A and 7B Latanoprost at day 1 and day 14,respectively, according to embodiments of the present invention.

FIG. 8 shows elution profiles of cyclosporine from drug cores into abuffer solution with surfactant and a buffer solution with surfactant,according to embodiments of the present invention.

FIG. 9 shows normalized elution profiles in nano-grams per device perday over 100 days for bulk sample of silicone with 1% Bimatoprost,according to embodiments of the present invention.

FIG. 10 shows profiles of elution of Latanoprost from the cores for fourformulations of Latanoprost, according to embodiments of the presentinvention.

FIG. 11A shows the effect on elution of material and crosslinking ondrug cores with 20% latanoprost, according to embodiments of the presentinvention.

FIG. 11B shows the effect of drug concentration on the elution oflatanoprost, according to embodiments of the present invention.

FIG. 11C shows the effect of covering one end of the drug core insert,according to embodiments of the present invention.

FIG. 12 shows the elution of fluorescein and the effect of surfactant onfluorescein elution, according to embodiments of the present invention.

FIG. 13 shows the elution of sterilized and non-sterilized drug cores,according to embodiments of the present invention.

FIG. 14 shows the effect of salt on the elution of therapeutic agent,according to embodiments of the present invention.

FIGS. 15 A-D shows scanning electron micrographs of longitudinalsections of a silicone/latanoprost drug insert prepared by a method ofthe invention; A, B,=extrusion at ambient and superambient temperatures;C, D=extrusion at subambient temperatures.

FIG. 16 shows a plot of latanoprost content per 1 mm section of a filledprecursor sheath prepared by an extrusion method which was carried outat about 0 degrees, about −25, about 40, and room temperatures.

FIGS. 17 shows an implant comprising a silicone body, a drug core andretention structures, according to embodiments of the present invention.

FIG. 18A shows a sectional view of a sustained release implant having afirst drug core with a first therapeutic agent and a second drug corewith a second therapeutic agent to treat an eye, the first and seconddrug cores being in a concentric configuration, according to anembodiment of the present invention.

FIG. 18B shows a side cross-sectional view of the sustained releaseimplant of FIG. 18A.

FIG. 19A shows a sectional view of a sustained release implant having afirst drug core with a first therapeutic agent and a second drug corewith a second therapeutic agent to treat an eye, the first and seconddrug cores being in a side by side configuration, according to anembodiment of the present invention.

FIG. 19B shows a side cross-sectional view of the sustained releaseimplant of FIG. 19A.

FIG. 20A shows a sectional view of a sustained release implant having afirst drug core with a first therapeutic agent and a second drug corewith a second therapeutic agent to treat an eye, the first and seconddrug cores being in a concentric configuration with a hollow center toallow fluid flow through the implant, according to an embodiment of thepresent invention.

FIG. 20B shows a side cross-sectional view of the sustained releaseimplant of FIG. 20A.

FIG. 2I schematically illustrates a lacrimal insert in the shape of apunctal plug for use in a therapeutic implant.

FIG. 22 shows one embodiment of a therapeutic implant to treat an eyehaving a punctal plug and a sustained release implant having a drug corewith a first therapeutic agent and a second therapeutic agent.

FIGS. 23-25 show different embodiments of therapeutic implants to treatan eye having a punctual plug and a sustained release implant having afirst drug core with a first therapeutic agent and a second drug corehaving a second therapeutic agent.

FIGS. 26A-26C show different embodiments of therapeutic implants totreat an eye that encompass punctual plugs made of amedication-impregnable porous material having with two therapeuticagents.

FIG. 27 shows therapeutic implants containing first and secondtherapeutic agents as applied to the eye.

FIG. 28 shows various core elements that are combinable into acylindrical shaped drug core.

FIGS. 29A-29D show different embodiments of a cylindrical shaped drugcore using the core elements of FIG. 28.

FIGS. 30A and 30B show other embodiments of a cylindrical shaped drugcore assembled from core elements of different shapes.

FIG. 31 shows a sectional view of a sustained release implant having afirst drug core with a first therapeutic agent and a second drug corewith a second therapeutic agents to treat an eye, the first and seconddrug cores being in a stacked configuration, according to an embodimentof the present invention.

FIG. 32 shows one embodiment of a therapeutic implant to treat an eyehaving a punctal plug and a sustained release implant having a firstdrug core with a first therapeutic agent and a second drug core having asecond therapeutic agent, the first and second drug cores being in astacked configuration, according to an embodiment of the presentinvention.

FIG. 33 shows one embodiment of a therapeutic implant to treat a bodycondition, the implant having a first therapeutic agent and a secondtherapeutic agent.

FIGS. 34 and 35 show anatomical tissue structures of the eye suitablefor use with implants, according to embodiments of the presentinvention.

FIG. 36 shows one embodiment of the implant having the bent design.

DETAILED DESCRIPTION Definitions

Unless otherwise indicated, the words and phrases presented in thisdocument have their ordinary meanings to one of skill in the art. Suchordinary meanings can be obtained by reference to their use in the artand by reference to general and scientific dictionaries, for example,Webster's Third New International Dictionary, Merriam-Webster Inc,Springfield, Mass., 1993, The American Heritage Dictionary of theEnglish Language, Houghton Mifflin, Boston Mass., 1981, and Hawley'sCondensed Chemical Dictionary, 14^(th) edition, Wiley Europe, 2002.

The following explanations of certain terms are meant to be illustrativerather than exhaustive. These terms have their ordinary meanings givenby usage in the art and in addition include the following explanations.

As used herein, the term “about” refers to a variation of 10 percent ofthe value specified; for example about 50 percent carries a variationfrom 45 to 55 percent.

As used herein, the term “and/or” refers to any one of the items, anycombination of the items, or all of the items with which this term isassociated.

As used herein, the singular forms “a,” “an,” and “the” include pluralreference unless the context clearly dictates otherwise.

“Subject” or “patient” as used herein, includes mammals such as humans,non-human primates, rats, mice, dogs, cats, horses, cows and pigs.

A “therapeutic agent” is a medicinal compound or mixture thereof that iseffective and medically indicated for treatment of a malcondition in apatient.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder or disease, orinhibition of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder. Similarly, as usedherein, an “effective amount” in the context of a therapeutic agent, ora “therapeutically effective amount” of a therapeutic agent refers to anamount of the agent that alleviates, in whole or in part, symptomsassociated with the disorder or condition, or halts or slows furtherprogression or worsening of those symptoms, or prevents or providesprophylaxis for the disorder or condition. In particular, an “effectiveamount” refers to an amount effective, at dosages and for periods oftime necessary, to achieve the desired therapeutic result. Atherapeutically effective amount is also one in which any toxic ordetrimental effects of compounds of the invention are outweighed by thetherapeutically beneficial effects. When the term “effective amount” isused in the context of a functional material, such as an effectiveamount of a dispersant, what is meant is that the amount of thefunctional material used is effective to achieve the desired result.

An “implant” as the term is used herein refers to a physical deviceadapted for insertion within or adjacent to a portion of a patient'sbody, not necessarily by surgical emplacement. For example, insertion ofan implant such as a punctal plug through the punctum into thecanaliculus of the eye of a patient need not involve surgicalintervention, similarly with the emplacement of a device adapted to beheld under an eyelid in contact with the orb of the eye. An implant isformed of biocompatible materials to the extent the materials actuallycome in contact with body tissues or fluids when disposed in theiroperative location. As defined herein, an implant is adapted to receivea “drug insert”, that is, a structure that contains the therapeuticagent to be administered to the particular patient for treatment of theparticular condition, and which is adapted to release the therapeuticagent to the target tissues or organs over a period of time. Release oftherapeutic quantities of an agent over a period of time is referred toas “sustained release” or “controlled release”, as is well known in theart.

By the terms “eye and surrounding tissues” is meant not just the orb ofthe eye, but surrounding conjunctival membranes, tear ducts, canaliculi(ducts draining tear liquid to the sinus), eyelids, and associated bodystructures.

A “polymer” as the term is used herein, refers to an organicmacromolecule containing one or more repeating units, as is well knownin the art. A “copolymer” refers to a polymer in which there are atleast two types of repeating units included. A copolymer can be a blockcopolymer, in which there are segments containing multiple repeatingunits of one type, bonded to segments containing multiple repeatingunits of a second type. A “polymer” or “polymeric material” can be asilicone, a polyurethane, a polyamide, a polyester, a polysaccharide, apolyimide, or the like, or any copolymer thereof. When a polymericmaterial is to come in contact with a body tissue or fluid, thepolymeric material is biocompatible.

A “matrix” is a material comprising an organic polymer in which thetherapeutic agent is dispersed, the combination of which materials,referred to as a “core”, serves as the reservoir of the agent from whichthe agent is released over a period of time.

The term “precursor” as used in the context of this invention and asapplied to any particular item means an intermediate or forerunner orprior article, device, item, or compound that is subsequentlymanipulated to form a final article, device, item or compound, or thelike. For example, a “precursor sheath” is the elongated tube that, whenfilled with matrix and then cut, forms the sheath of the insert. Inanother example in the language used herein, a “matrix precursor” is“cured” to form the matrix. The matrix precursor can itself be apolymer, and can be cured, for example, by crosslinking. Or, the matrixprecursor can be a polymer dissolved in a solvent, and curing includesremoval of the solvent to provide the polymeric matrix material. Or, thematrix precursor can be a monomer, and curing can involve polymerizationof the monomer, and can also involve removal of a solvent, andcrosslinking of a polymer formed by polymerization. In a furtherexample, a precursor drug core is a cured matrix containing thetherapeutic agent that can be cut into appropriate lengths to form adrug core. A typical application of the precursor drug core is thefilled precursor sheath. The filled precursor sheath is a precursorsheath body containing the precursor drug core that can be cut intoappropriate lengths thereby producing a drug insert of the invention.

The terms “agent”, “therapeutic agent”, or “drug” as used herein referto a medicinal material, a compound or a mixture thereof, suitable andmedically indicated for treatment of a malcondition in a patient. Theagent can be in a solid physical form or a liquid physical form at aboutroom temperature or at about body temperature, depending on the meltingpoint of the material. Examples of therapeutic agents are providedherein; for treatment of malconditions of the eye, specific examples oftypes or classes of agents that can be included in the inventive insertsinclude a glaucoma medication, a muscarinic agent, a beta blocker, analpha agonist, a carbonic anhydrase inhibitor, or a prostaglandin orprostaglandin analog; an antiinflammatory agent; an anti- infectiveagent; a dry eye medication; or any combination thereof. Morespecifically, an example of a glaucoma medication is a prostaglandin ora prostaglandin analog. An example of a muscarinic agent is pilocarpine.An example of a beta blocked is betaxolol. An example of an alphaagonist is brimonidine. Examples of a carbonic anhydrase inhibitor aredorzolamide or brinzolamide. Examples of an antiinflammatory agentinclude a steroid, a soft steroid, or an non-steroidal antiinflammatorydrug (NSAID) such as ibuprofen. An example of an analgesic includes,salicylic acid and acetaminophen. An antibiotic (antibacterial) can be abeta-lactam antibiotic, a macrocyclic antibiotic such as erythromycin, afluoroquinolone, or the like. An antiviral compound can be a reversetranscriptase inhibitor or a viral protease inhibitor. An antimycoticcan be a triazole antifungal compound. A dry eye medication can becyclosporine, olapatadine, a delmulcent, or sodium hyaluronate.

In various embodiments, the therapeutic agent is contained in the matrixsuch that an amount of the therapeutic agent in a volumetric portion ofthe drug core is similar to an amount of the therapeutic agent in anyother equal volumetric portion of the drug core. For example, the amountof the therapeutic agent in a volumetric portion of the drug core canvary from the amount of the therapeutic agent in any other equalvolumetric portion of the drug core by no greater than about 30%. Forexample, the amount of the therapeutic agent in a volumetric portion ofthe drug core can vary from the amount of the therapeutic agent in anyother equal volumetric portion of the drug core by no greater than about20%. For example, the amount of the therapeutic agent in a volumetricportion of the drug core can vary from the amount of the therapeuticagent in any other equal volumetric portion of the drug core by nogreater than about 10%. For example, the amount of the therapeutic agentin a volumetric portion of the drug core can vary from the amount of thetherapeutic agent in any other equal volumetric portion of the drug coreby no greater than about 5%. In addition, the concentration of thetherapeutic agent in a volumetric portion of the drug core can be thesame as any other equal volumetric portion of the drug core, in certainembodiments including those embodiments wherein the agent is present asa uniform, homogeneous dispersion and in embodiments wherein the agentis present in solid or liquid inclusions throughout the matrix.

The agent can be dissolved in the matrix in some embodiments, when thechemical identities of the agent and the matrix, and the concentrationof the agent in the matrix, are such that dissolution is achieved. Forexample, as is known in the art, certain lipophilic steroid derivativescan dissolve at significant concentrations in silicones. In this event,the agent is referred to as being “dissolved” in the polymer, or asbeing uniformly, homogeneously dispersed throughout the matrix or“dispersed at a molecular level” in the polymer, just as a compound canbe dissolved in a solvent, to form a “solid solution” of the agent inthe polymeric material of the matrix.

In other embodiments, the agent does not completely dissolve in thematrix, but is present as domains or “inclusions” of the agent withinthe polymeric matrix. The inclusions can be liquid or solid at aboutroom temperature or at about the temperature of the human body. Afterthe matrix precursor has been cured to form the matrix, the inclusionsare non-uniformly distributed in the now-solid or near solid matrix, andare thus prevented at least to some extent from recombining with eachother, such as by liquid droplet accretion. This form is referred to asa “heterogeneous” distribution of the agent in the matrix. Wheninclusions of the agent are present, it is believed that a certainproportion of the agent may also be dissolved in the matrix. However,dissolution is not necessary for operation and function of theinvention. Furthermore, the heterogeneous distribution of the agent withthe matrix can be managed on a macroscopic level as discussed inconnection with the definition of the terms “concentration” and“similar” given below.

A “concentration” of a therapeutic agent, as the term is used herein,refers to a concentration of the agent within a macroscopic portion ofthe matrix-agent core, that is controlled to have a degree ofreproducibility from sample to sample of the core. A concentration ofthe agent in a macroscopic portion of the core can vary, but only withinlimits, relative to that in any other equal macroscopic portion of thecore. The term does not relate to concentrations at the molecular level,where discontinuous and/or irregular domains or inclusions of the agentin concentrated form may be present, but rather refers to bulkconcentrations of the agent in volumes of the core that are greater thanat least about 0 1 mm³, for example, a cubic sample of core about 100 μmon a side, or a 0.1 mm thick slice of a core with cross-sectional areaof about 1 mm².

The term “similar”, as in a “similar” concentration of a therapeuticagent, means that within a defined margin, the quantity, such as theconcentration of the agent, for example in units of μg/mm³, only varieswithin a certain degree from measurement to measurement. The degree ofvariation is controlled or regulated to provide a degree of uniformityof core material, such that pluralities of cores or inserts aremedically suitable in that the dose of the agent they can provide to thetissue is within certain limits from sample to sample. For example, a“similar” concentration between two equal volumes of core material, orbetween two inserts prepared by from a filled precursor sheath, can varyby no greater than about 30%, or can vary by no greater than about 20%,or can vary by no greater than about 10%, or can vary by no greater thanabout 5%. The term “similar” also includes solid solutions and uniformhomogeneous dispersions, defined herein. These concern situations wherethe concentration of the therapeutic agent is the same in differentportions of the core or between a plurality of cores. This is asubcategory of the more general category “similar.”

The inclusions can be of various sizes, and various distributions ofsizes of a plurality of the inclusions are possible, as are definedherein. When it is stated that the inclusions are no greater than about100 μm in diameter, what is meant is that the largest inclusion observedwithin a drug insert of the invention has a greatest dimension of nogreater than about 100 μm. When a particular size distribution ofinclusions is recited, what is meant is that a predominant proportion ofall the inclusions are of the stated dimension. When an average size or“average diameter” of inclusions within a population of inclusions isstated, what is meant is a numerical average of the greatest dimensionsof all the inclusions. When a “standard deviation” of the distributionof inclusion diameters with in a population of inclusions is stated,what is meant that the distribution of inclusion diameters is normal ornear normal, and that the standard deviation is a measure of the spreadof the values, as is well known in the art. A small standard deviationrelative to the average diameter denotes a tight distribution ofinclusion diameters, a feature of various embodiments of the presentinvention.

In various embodiments, the inclusions can have an average diameter ofless than about 20 μm, and a standard deviation of diameters of theinclusions is less than about 8 μm. Or, the inclusions can have anaverage diameter of less than about 15 μm, and a standard deviation ofdiameters of the inclusions is less than about 6 μm. Or, the inclusionscan have an average diameter of less than about 10 μm, and a standarddeviation of diameters of the inclusions is less than about 4 μm. Arelative uniformity of inclusion size distribution, and a relativeuniformity of the amount of agent dispersed per unit volume of the corewithin the insert, are features of various embodiments according to thepresent invention.

The size distribution of inclusion diameters can be monodisperse, andcan be tightly so. By “monodisperse” is meant herein that the sizedistribution of the diameters of the plurality of inclusions isrelatively tightly clustered around the average inclusion diameter, evenif the distribution is not a normal distribution. For example, thedistribution can have a fairly sharp upper size limit of inclusions ofgreater than average diameter, but can trail off in the distribution ofinclusions of less than average diameter. Nevertheless, the sizedistribution can be tightly clustered, or monodisperse.

A “polyurethane” refers to a variety of polymer or copolymer containingrepeating units bonded covalently through urethane, i.e., carbamate,bonds, —N—C(O)—O— wherein the N and O atoms are attached to an organicradical. The organic radical can be aliphatic, aromatic, or mixed; cancontain other functional groups. Each radical, other than the radicalsat the ends of the molecular chains, is bonded via two (or more)urethane groups to other radicals. A polyurethane polymer contains onlyurethane-type groups joining the repeating units. A polyurethanecopolymer, such as a polyurethane-silicone copolymer or apolyurethane-carbonate copolymer, contains urethane and other types ofgroups joining the repeating units, i.e., silicone and carbonate typegroups respectively.

A polyurethane-silicone copolymer contains segments of polyurethanechains and segments of silicone chains, as is well known in the art. Apolyurethane-carbonate copolymer contains urethane segments andcarbonate (—O—C(O)O—) segments. An example of a polyurethane-carbonatecopolymer is Carbothane TPU® (Lubrizol).

A “hydrogel” as the term is used herein refers to a polymeric materialthat has absorbed greater than 100 wt %, for example up to 500-2000 wt%, of water within the polymeric structure and has consequently swelledsubstantially in physical size. A hydrogel possesses physical integrity,has tensile strength, and is not substantially fluid. A“hydrogel-forming polymer” is a polymeric material capable of forming ahydrogel upon contact with water. Examples include TG-500 and TG-2000.

“TG-500” and “TG-2000” are polyurethane hydrogel-forming polymersmanufactured by the Thermedics Polymer Products division of LubrizolAdvanced Materials, Inc., of Wilmington, Mass. They are described by themanufacturer as aliphatic, polyether based thermoplastic polyurethanescapable of forming hydrogels. Such hydrogel-forming polymers can absorbgreater than 100 wt %, for example up to 500-2000 wt % of water, andconsequently swell in physical dimensions.

A “hydrophilic polymer” is a polymer that can be wetted by water, i.e.,does not have a water-repellant surface. A hydrophilic polymer canabsorb water to a small degree, for example about 0-100 wt % of water,but does not greatly swell in volume as does a hydrogel-forming polymer.

“Cyclosporine” is an immunosuppressant drug widely used inpost-allogeneic organ transplant to reduce the activity of the patient'simmune system and so the risk of organ rejection. It has been studied intransplants of skin, heart, kidney, lung, pancreas, bone marrow andsmall intestine. Initially isolated from a Norwegian soil sample,Cyclosporin A, the main form of the drug, is a cyclic nonribosomalpeptide of 11 amino acids (an undecapeptide) produced by the fungusTolypocladium inflatum Gams. The structure of cyclosporine is:

“Olopatadine”, the structure of which is shown below, is a NSAID thatcan be administered in the form of a hydrochloride salt:

A “prodrug” is a substance, for example, that releases a therapeuticagent such as cyclosporine or olopatidine, or a biologically activederivative of either of these substances, when administered to a mammal.A prodrug can be a chemical derivative that contains a bond that iscleavable by an endogenous enzyme of the mammalian circulatory systemsuch as an esterase or a phosphatase. For example, an amide NH ofcyclosporine can be substituted with an ester group, providing acarbamate of structure ROC(O)N-cyclosporine. An endogenous esterase cancleave the ester bond, yielding an N-carboxyamide, which canspontaneously decarboxylate to yield cyclosporine. An ester ofolopatidine, which can be cleaved by an endogenous esterase to yieldolopatidine, is an example of an olopatidine prodrug. By formation ofprodrugs, the polarity (hydrophobicity/hydrophilicity) of cyclosporineor olopatidine can be modified.

A “derivative” is a substance chemically allied to the therapeuticagent, and retaining at least some of the therapeutic agent's biologicalactivity, but which need not be metabolized to the agent itself in themammalian body to provide the desired beneficial result.

A “release profile”, as in a “defined release profile”, refers to a rateof release as a function of time of the therapeutic agent from aninventive plug into the eye, which can be defined or determined byselection of a particular polyurethane polymer or copolymer for aparticular therapeutic agent. The release profile will in turn governboth the concentration of the agent in the eye and surrounding tissueover the time period during which the plug releases the agent.

Detailed Description

The present invention is directed to various embodiments of drug insertsand drug cores containing therapeutic agents for use in implant bodiesadapted for disposition in a body tissue, fluid, cavity, or duct. Theimplant bodies can be adapted to be disposed in or adjacent to an eye ofa patient. The implants release the agent to the body, for example, intoan eye or surrounding tissues, or both, over a period of time, fortreatment of a malcondition in the patient for which use of thetherapeutic agent is medically indicated. The invention is also directedto various embodiments of methods of manufacture of the drug inserts,and to methods of treatment of patients using implants containing thedrug inserts.

In various embodiments, the invention provides a drug core adapted fordisposition within a sheath and hence within an implant. The implant isadapted for disposition within or adjacent to an eye of a patient, forproviding sustained release of a therapeutic agent to the eye orsurrounding tissues or both.

The drug core comprises a therapeutic agent and a matrix wherein thematrix comprises a polymer, wherein an amount of the therapeutic agentin a volumetric portion of the drug core is similar to an amount of thetherapeutic agent in any other equal volumetric portion of the drugcore.

The insert comprises a drug core and a sheath body partially coveringthe drug core. For example, the amount of the therapeutic agent withinthe volumetric portion of the drug core varies from the amount of thetherapeutic agent within any other equal volumetric portion of the drugcore by less than about 30%. For example, the amount of the therapeuticagent within the volumetric portion of the drug core varies from theamount of the therapeutic agent within any other equal volumetricportion of the drug core by less than about 20%. For example, the amountof the therapeutic agent within the volumetric portion of the drug corevaries from the amount of the therapeutic agent within any other equalvolumetric portion of the drug core by less than about 10%. For example,the amount of the therapeutic agent within the volumetric portion of thedrug core varies from the amount of the therapeutic agent within anyother equal volumetric portion of the drug core by less than about 5%.

The sheath body is disposed over a portion of the drug core to inhibitrelease of the agent from said portion and so as to define at least oneexposed surface of the drug core adapted to release the agent to the eyeor surrounding tissues, or both, when the implant is inserted into thepatient.

In various embodiments, the invention provides a plurality of the druginserts as described above wherein each of the plurality of the insertscomprises a similar amount of the agent dispersed respectivelytherewithin For example, the similar amount of agent dispersedrespectively therein can vary no greater than about 30% therebetween.For example, the similar amount of agent dispersed respectively thereincan vary no greater than about 20% therebetween. For example, thesimilar amount of agent dispersed respectively therein can vary nogreater than about 10% therebetween. For example, the similar amount ofagent dispersed respectively therein can vary no greater than about 5%therebetween.

The exposed surface of the core is adapted to release therapeuticquantities of the agent into body tissues or fluids, for example intotear liquid, for a time period of at least several days into tear liquidwhen the implant is inserted into the patient. The sheath, which isimpermeable to the agent, serves to block, at least in part, exposure ofnon-target tissues to the agent. For example, when the drug insert isdisposed within an implant inserted into the canaliculus of the eye, thesheath acts to inhibit the release of the agent to the therapeutictarget, e.g., the eye, while blocking release to non-target tissue, suchas the interior of the canaliculus, or the nasal sinus.

In an embodiment, the drug core can be substantially cylindrical inform, having an axis, wherein the exposed surface of the drug core isdisposed on one end of the cylindrical form and a surface of the drugcore covered by the sheath body constitutes a remainder of the surfaceof the cylindrical form.

In a plurality of drug inserts of the invention, the therapeuticquantity of the agent released by each of the drug inserts is similarfrom one insert to another. For example, among a plurality of druginserts of the invention, the therapeutic quantity of the agent releasedby each of the plurality of the inserts can vary by no greater thanabout 30% therebetween, or by no greater than about 20% therebetween, orby no greater than about 10% therebetween, or by no greater than about5% therebetween. In some embodiments, among a plurality of drug insertsof the invention, the therapeutic quantity of the agent released by eachof the plurality of the inserts can be the same.

The drug core or drug insert can have various relative contents of thetherapeutic agent therein. For example, the drug core can include about0.1 wt % to about 50 wt % of the agent. The agent is dispersed withinthe matrix, the matrix comprising a polymer, to form a compositematerial that can be disposed within the sheath. For example, the matrixcan be formed of a non-biodegradable silicone or a polyurethane, orcombination thereof. The sheath is formed of a substantiallydrug-impermeable substance to block release of the agent except throughan exposed surface. It can be formed of any suitable biocompatiblematerial, such as a polymer comprising at least one of polyimide, PMMA,or PET, wherein the polymer is extruded or cast; or a metal comprisingstainless steel or titanium.

A therapeutic agent for use in the inventive insert or core can includeanti-glaucoma medications, (e.g. adrenergic agonists, adrenergicantagonists (beta blockers), carbonic anhydrase inhibitors (CAIs,systemic and topical), parasympathomimetics, prostaglandins such aslatanoprost, and hypotensive lipids, and combinations thereof),antimicrobial agent (e.g., antibiotic, antiviral, antiparasitic,antimycotic, etc.), a corticosteroid or other anti-inflammatory (e.g.,an NSAID or other analgesic and pain management compounds) such ascyclosporine or olopatidine, a decongestant (e.g., vasoconstrictor), anagent that prevents of modifies an allergic response (e.g., anantihistamine, cytokine inhibitor, leucotriene inhibitor, IgE inhibitor,immunomodulator such as cyclosporine), a mast cell stabilizer,cycloplegic, mydriatic or the like.

Examples of agents further include, but are not limited to, thrombininhibitors; antithrombogenic agents; thrombolytic agents; fibrinolyticagents; vasospasm inhibitors; vasodilators; antihypertensive agents;antimicrobial agents, such as antibiotics (such as tetracycline,chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin,tobramycin, gentamycin, erythromycin, penicillin, sulfonamides,sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole,nitrofurazone, sodium propionate), antifungals (such as amphotericin Band miconazole), and antivirals (such as idoxuridine trifluorothymidine,acyclovir, gancyclovir, interferon); inhibitors of surface glycoproteinreceptors; antiplatelet agents; antimitotics; microtubule inhibitors;anti-secretory agents; active inhibitors; remodeling inhibitors;antisense nucleotides; anti-metabolites; antiproliferatives (includingantiangiogenesis agents); anticancer chemotherapeutic agents;anti-inflammatories (such as cyclosporine, olopatidine, hydrocortisone,hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone,medrysone, methylprednisolone, prednisolone 21-phosphate, prednisoloneacetate, fluoromethalone, betamethasone, triamcinolone, triamcinoloneacetonide); non steroidal anti-inflammatories (NSAIDs) (such assalicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicamindomethacin, ibuprofen, naxopren, piroxicam and nabumetone). Examplesof such anti-inflammatory steroids contemplated for use with the presentpunctum plugs, include triamcinolone acetonide and corticosteroids thatinclude, for example, triamcinolone, dexamethasone, fluocinolone,cortisone, prednisolone, flumetholone, and derivatives thereof);antiallergenics (such as sodium chromoglycate, antazoline,methapyriline, chlorpheniramine, cetrizine, pyrilamine,prophenpyridamine); anti proliferative agents (such as 1,3-cis retinoicacid, 5-fluorouracil, taxol, rapamycin, mitomycin C and cisplatin);decongestants (such as phenylephrine, naphazoline, tetrahydrazoline);miotics and anti-cholinesterase (such as pilocarpine, salicylate,carbachol, acetylcholine chloride, physostigmine, eserine, diisopropylfluorophosphate, phospholine iodine, demecarium bromide);antineoplastics (such as carmustine, cisplatin, fluorouracil);immunological drugs (such as vaccines and immune stimulants); hormonalagents (such as estrogens, estradiol, progestational, progesterone,insulin, calcitonin, parathyroid hormone, peptide and vasopressinhypothalamus releasing factor); immunosuppressive agents, growth hormoneantagonists, growth factors (such as epidermal growth factor, fibroblastgrowth factor, platelet derived growth factor, transforming growthfactor beta, somatotrapin, fibronectin); inhibitors of angiogenesis(such as angiostatin, anecortave acetate, thrombospondin, anti-VEGFantibody); dopamine agonists; radiotherapeutic agents; peptides;proteins; enzymes; extracellular matrix; components; ACE inhibitors;free radical scavengers; chelators; antioxidants; anti polymerases;photodynamic therapy agents; gene therapy agents; and other therapeuticagents such as prostaglandins, antiprostaglandins, prostaglandinprecursors, including antiglaucoma drugs including beta-blockers such astimolol, betaxolol, levobunolol, atenolol, and prostaglandin analoguessuch as bimatoprost, travoprost, latanoprost etc; carbonic anhydraseinhibitors such as acetazolamide, dorzolamide, brinzolamide,methazolamide, dichlorphenamide, diamox; and neuroprotectants such aslubezole, nimodipine and related compounds; and parasympathomimetricssuch as pilocarpine, carbachol, physostigmine and the like.

Additional agents that can be used with the present implants include,but are not limited to, drugs that have been approved under Section 505of the United States Federal Food, Drug, and Cosmetic Act or under thePublic Health Service Act, some of which can be found at the U.S. Foodand Drug Administration (FDA) websitehttp://www.accessdata.fda.gov/scripts/cder/drugsatfda/index. The presentpunctum plugs can also be used with drugs listed in the Orange Book,either in paper or in electronic form, which can be found at the FDAOrange Book website (http://www.fda.gov/cder/ob/)), that has or recordsthe same date as, earlier date than, or later date than, the filing dateof this patent document. For example, these drugs can include, amongothers, dorzolamide, olopatadine, travoprost, bimatoprost, cyclosporin,brimonidine, moxifloxacin, tobramycin, brinzolamide, aciclovir timololmaleate, ketorolac tromethamine, prednisolone acetate, sodiumhyaluronate, nepafenac, bromfenac,diclofenac, flurbiprofen, suprofenac,binoxan, patanol, dexamethasone/tobramycin combination, moxifloxacin, oracyclovir.

In various embodiments, a agent can be cyclosporine, or a prodrug orderivative thereof, or olopatidine, or a prodrug or derivative thereof,and, optionally, a second agent selected from the above-listedtherapeutic agents.

In various embodiments, the agent can be a prostaglandin analog, such aslatanoprost, bimatoprost, or travoprost, and the amount of the agent inthe drug insert can be about 10-50 μg.

In various embodiments, the therapeutic agent is contained in the matrixsuch that an amount of the therapeutic agent in a volumetric portion ofthe drug core is similar to an amount of the therapeutic agent in anyother equal volumetric portion of the drug core. For example, the amountof the therapeutic agent in a volumetric portion of the drug core canvary from the amount of the therapeutic agent in any other equalvolumetric portion of the drug core by no greater than about 30%. Forexample, the amount of the therapeutic agent in a volumetric portion ofthe drug core can vary from the amount of the therapeutic agent in anyother equal volumetric portion of the drug core by no greater than about20%. For example, the amount of the therapeutic agent in a volumetricportion of the drug core can vary from the amount of the therapeuticagent in any other equal volumetric portion of the drug core by nogreater than about 10%. For example, the amount of the therapeutic agentin a volumetric portion of the drug core can vary from the amount of thetherapeutic agent in any other equal volumetric portion of the drug coreby no greater than about 5%. In addition, the concentration of thetherapeutic agent in a volumetric portion of the drug core can be thesame as any other equal volumetric portion of the drug core, in certainembodiments including those embodiments wherein the agent is present asa uniform, homogeneous dispersion and in embodiments wherein the agentis present in solid or liquid inclusions throughout the matrix.

In various embodiments, the agent can be dissolved in the matrix withinthe drug core, i.e., at an effective concentration for use as with animplant, wherein the agent is sufficiently soluble in the polymer suchthat no inclusions or concentrated domains of the agent are present.This is known in the art as a solid solution, i.e. a uniform,homogeneous dispersion on the molecular level, wherein the solid polymerplays the role of a solvent, and no liquid solvent is present. Forexample, when the agent comprises cyclosporine and the matrix comprisespolyurethane, a solid solution is formed at useful concentrations of thecyclosporine in the insert. This solubility is believed to result, atleast in part, from interaction of the abundant amide bonds found in thecyclosporine molecule, which is a cyclic peptide, with the amide-likeurethane bonds of the polyurethane polymer.

In various embodiments, the agent is insufficiently soluble in thematrix to form a solid solution. In these embodiments, the agent can bedistributed at least in part as a plurality of solid or liquidinclusions throughout the matrix, the inclusions comprising, at atemperature of about 20° C., droplets of the agent of no greater thanabout 100 μm diameter when the agent is a liquid at about 20° C., orparticles of the agent of no greater than about 100 p.m diameter whenthe agent is a solid at about 20° C.; wherein the inclusions of theagent are dispersed throughout each drug core.

As discussed above, the size and size distribution of the inclusions canhave an effect on a rate of release of the agent from the drug core tothe patient. For example, smaller, more uniform inclusions can serve toinfuse the bulk matrix with the agent more effectively, at a higherrate, due to a more favorable surface area to volume ratio. Accordingly,inventive methods provide for control or regulation of the averageinclusion diameter or the distribution of inclusion diameters. Forexample, the inclusions can have an average diameter of less than about20 μm. Inclusions of this average diameter can have a standard deviationof diameters of the inclusions of less than about 8 μm. For example, theinclusions can have an average diameter of less than about 15 μm.Inclusions of this average diameter can have a standard deviation ofdiameters of the inclusions of less than about 6 μm. Or, the inclusionscan have an average diameter of less than about 10 μm. Inclusions ofthis average diameter can have a standard deviation of diameters of theinclusions of less than about 4 μm. In various embodiments, thedistribution of diameters of the inclusions can be a monodispersedistribution. In various embodiments, the inclusions predominantlycomprise a cross-sectional size within a range from about 0.1 μm toabout 50 μm. It is believed that tight, or monodisperse, distributionsof inclusion diameter are favorable from the point of view oftherapeutic aspects of the drug core or a drug insert containing thecore.

Various embodiments of the invention also provide a drug core or aninsert containing a drug core wherein the agent forms inclusions in thematrix that are in a liquid physical state at about 20° C. For example,substantially all the inclusions can be droplets of the agent of lessthan about 30 μm in diameter within the matrix. And, the droplets canhave an average diameter of less than about 10 μm, or can have astandard deviation of diameters of the inclusions is less than about 4μm. An example of an agent in a liquid physical state at about 20° C. islatanoprost.

Various embodiments of the invention also provide a drug core or aninsert containing a drug core wherein the agent forms inclusions in thematrix that are in a solid physical state at about 20° C. For example,substantially all the inclusions can be particles of the agent of lessthan about 30 μm in diameter within the matrix. For example, an averageparticle diameter within the matrix can be about 5-50 μm. Examples ofagents in a solid physical state at about 20° C. include bimatoprost,olopatadine, or cyclosporine.

In various embodiments the drug insert or drug core can comprise two ormore therapeutic agents, or can comprise a plurality of drug cores. Sucha plurality of drug cores can also be termed a plurality of drugsub-cores which together form the total drug core. In this context firstand second drug cores can also be termed first and second drug sub-coresfor clarity purposes. For example, a drug insert of the invention caninclude two drug cores disposed within the sheath body, a first drugcore comprising a first agent and a first matrix, and a second drug corecomprising a second agent and a second matrix, wherein the first agentand the second agent are different, and wherein the first matrix and thesecond matrix are either the same or differ from each other; the implantbody comprising an aperture adapted to receive the first and the secondcores disposed within the sheath body, the drug cores being adapted tobe disposed, within the sheath, within the aperture of the implant body.The first matrix and the second matrix can differ from each other withrespect to at least one of a composition, an exposed surface area, asurfactant, a crosslinker, an additive, a matrix material, aformulation, a release rate modifying reagent, or a stability. The firstdrug core and the second drug core can be disposed within the sheathbody such that the first drug core has a surface exposed directly totear liquid and the second drug core does not have a surface exposeddirectly to tear liquid when the drug insert is disposed within theimplant body and the implant body is disposed in or adjacent to the eyeof the patient. Or, the first drug core and the second drug core can bedisposed side by side within the sheath body. Or, the first drug coreand the second drug core can each be cylindrical in shape and bedisposed with the sheath body, the first drug core being positioned neara proximal end of an aperture in the implant body and the second drugcore being positioned near a distal end of the aperture, when the druginsert is disposed within the implant body. Or, the first drug core andthe second drug core can each be cylindrical in shape provided that thefirst drug core has a first central opening, the drug cores beingpositioned concentrically within the sheath body within an aperture ofthe implant body adapted to receive the drug insert, and the second drugcore being configured to fit within the first central opening of thefirst drug core. Or, the first and second drug cores can beconcentrically positioned within the aperture of the implant body, thefirst drug core having a first central opening exposing a first innersurface and the second drug core having a second central openingexposing a second inner surface, the second drug core being configuredto fit within the first central opening of the first drug core, andwherein the aperture extends from a proximal end to a distal end of theimplant body thereby being adapted to allow tear liquid to pass throughthe aperture and contact the first and second inner surfaces of thefirst and second central openings and release the first and secondtherapeutic agents into a canaliculus of the patient when the implantbody is inserted into a patient.

In various embodiments, the first therapeutic agent can have a releaseprofile wherein the first agent is released at therapeutic levelsthroughout a first time period and the second therapeutic agent can havea second release profile wherein the second agent is released attherapeutic levels throughout a second time period. For example, thefirst time period and the second time period can be between one week andfive years. The first release profile and the second release profile canbe substantially the same, or can be different.

In various embodiments, the first agent can provides a first effect anda side effect to the patient, and the second agent can provide a secondeffect that mitigates or counters the side effect of the first agent.

In various embodiments, any inclusions in the first drug core and in thesecond drug core respectively have an average diameter of less thanabout 20 μm, and can have a standard deviation of diameters of less thanabout 8 μm.

In various embodiments, the implant body can comprise a central borethat extends from a proximal end to a distal end of the implant body soas to be adapted to allow a tear liquid to pass through the implant bodysuch that the first and second therapeutic agents are released into thetear liquid into a canaliculus of the patient when the implant body isdisposed in or adjacent to the eye.

In various embodiments, the drug insert or the drug core can furtherinclude a medication-impregnated porous material within the firstmatrix, the second matrix, or both, wherein the medication-impregnatedporous material is adapted so as to permit tear liquid to release thefirst agent, the second agent, or both, from the medication-impregnatedporous material at therapeutic levels over a sustained period when adrug core-containing implant is disposed within a punctum or within alacrimal canaliculus, and wherein the medication-impregnated porousmaterial is a gel material that can swell from a first diameter to asecond diameter when in contact with tear liquid. The second diametercan be about 50% greater than the first diameter. An example of asuitable material for the medication-impregnated porous material is ahydroxyethylmethacrylate (HEMA) hydrophilic polymer.

In various embodiments, the drug insert or drug core can comprise apolyurethane polymer or copolymer. For example, the polyurethane polymeror copolymer can be an aliphatic polyurethane, an aromatic polyurethane,a polyurethane hydrogel-forming material, a hydrophilic polyurethane, ora combination thereof. In various embodiments, the polyurethane polymeror copolymer can include a hydrogel adapted to swell when contacted withan aqueous medium and the sheath body is adapted to be of sufficientelasticity to expand in response thereto. For example, the swelling canbe adapted to retain the implant body within a duct, such as within apunctal canal, of the patient.

In various embodiments, when the matrix comprises a polyurethane, thetherapeutic agent comprises cyclosporine or olopatadine, a prodrug or aderivative of cyclosporine or olopatadine, or any combination thereof.For example, the cyclosporine or the olopatadine, or the cyclosporineprodrug or derivative, or the olopatadine prodrug or derivative, or thecombination thereof, can be present in a weight ratio to thepolyurethane polymer or copolymer of about 1 wt % to about 70 wt %. Aconcentration of the cyclosporine in the core can be similar in aportion of the drug core proximate to the exposed surface, a portiondistal to the exposed surface, and a portion disposed between theproximate portion and the distal portion. For example, the proximalportion can be in length at least about one tenth a length of the drugcore.

In various embodiments, the invention provides a drug core comprising atherapeutic agent and a matrix wherein the matrix comprises a polymer,for disposition into a drug insert or an implant. The drug insert or theimplant is adapted for disposition within or adjacent to an eye of apatient for providing sustained release of the therapeutic agent to theeye or surrounding tissues or both. The therapeutic agent is containedin the matrix such that an amount of the therapeutic agent in avolumetric portion of the drug core is similar to an amount of thetherapeutic agent in any other equal volumetric portion of the drugcore. For example, the therapeutic agent may be either uniformlyhomogeneously dispersed throughout the matrix such as in a solidsolution, or the therapeutic agent at least in part forms solid orliquid inclusions within the matrix. For example, the amount of thetherapeutic agent in a volumetric portion of the drug core can vary fromthe amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 30%. For example, theamount of the therapeutic agent in a volumetric portion of the drug corecan vary from the amount of the therapeutic agent in any other equalvolumetric portion of the drug core by no greater than about 20%. Forexample, the amount of the therapeutic agent in a volumetric portion ofthe drug core can vary from the amount of the therapeutic agent in anyother equal volumetric portion of the drug core by no greater than about10%. For example, the amount of the therapeutic agent in a volumetricportion of the drug core can vary from the amount of the therapeuticagent in any other equal volumetric portion of the drug core by nogreater than about 5%. For example, the amount of the therapeutic agentin a volumetric portion of the drug core can be the same as the amountof therapeutic agent in any other equal volumetric portion of the drugcore.

In various embodiments of the inventive drug insert for an implant fordisposition in or adjacent to a patient's eye, the implant can be alacrimal implant insertable into a lacrimal canaliculus, which iscommonly referred to as a punctal plug, i.e., an implant adapted toinsertion through a punctum of the eye to reside within the canaliculusof the eye, wherein the drug insert can come in contact with tear liquidand thereby release the therapeutic agent for contact with the eye orsurrounding tissues or both.

In various embodiments, the core of the insert comprising the agent anda matrix, the matrix comprising a polymeric material, is surrounded by asheath body. The sheath body is substantially impermeable to the agent,such that the agent is released to the tear liquid only through anexposed surface of the core that comes in contact with the tear liquid.The agent contained within the core serves as a reservoir in order torelease therapeutic quantities or concentrations of the agent over aperiod of time, which can range from days to months. For example, intreatment of glaucoma, the drug insert can contain a prostaglandinanalog such as latanoprost.

The drug core is adapted to be disposed within a larger structure, animplant, which is in turn adapted for disposition within the bodytissue, cavity, or duct. In various embodiments, the implant can be apunctal plug adapted for emplacement within the canaliculus of the eye,that is, within the duct(s) that drain tears from the surface of theeye.

For example, various embodiments of the drug cores can be used inimplants, such as punctal plugs, adapted for placement near the eye totreat a patient suffering from a malcondition of the eye through therelease of one or more drugs from the core within the implant onto thesurface of the eye, such as by diffusion into tear fluids. Althoughspecific reference is made to punctal plugs with drug deliverycapabilities for use within the canaliculus of the eye, variousembodiments of the implants may be useful for sustained release of thedrug and treatment of other structures near and/or within the eye, forexample the sclera, the conjunctiva, the cul-de-sac of the eyelid, thetrabecular meshwork, the ciliary body, the cornea, the choroid, thesuprachoroidal space, the sclera, the vitreous humor, aqueous humor andretina. Also, the inventive implants with their cores can be used forrelease of therapeutic agents into tissues, body cavities, or ducts,other than an eye or adjacent structures. In various embodiments, thedrug cores can be used for sustained release of therapeutic agents intothe ears and/or Eustachian tubes, nasal and/or sinus cavities, urethra,skin, gastrointestinal tract (including colon, bowel duct, and thelike), and in or near joints such as knee, finger, and intervertebraljoints.

In various embodiments, a drug core comprising a composite of atherapeutic agent and a matrix is partially contained within orsurrounded by a sheath, the sheath being substantially impermeable tothe agent. The sheath can cover part, but not all, of the surface of thecore comprising the drug and the matrix material, the core having anexposed surface such that the therapeutic agent can be releasedtherethrough. The drug core and its sheath together are adapted forinclusion within an implant structure that is itself adapted forimplantation within a body of a patient, such as within a body cavity,tissue, duct, or fluid. For example, the implant can be an ocularimplant, adapted for disposition in or around the eye, such as a punctalplug, adapted to disposition within the canaliculus of the eye such thatthe agent can be released through the punctum of the eye to contact theorb and surrounding tissues.

The sheath can be composed of any suitable biocompatible material whichis substantially impermeable to the therapeutic agent. For example, thesheath can be an impermeable polymeric material such as a polyimide,polymethylmethacrylate, or a polyester such as PET, or a biocompatiblemetal such as stainless steel or titanium, or an inorganic glass, suchas formed from silicon oxide. The agent can be any therapeutic substancecapable of at least some diffusion through the matrix, which comprises apolymer, such that the agent can be released into a body tissue orfluid. A matrix can comprise a polymeric material, for example, thematrix can include a silicone, a polyurethane, or any non-biodegradablepolymer wherein the agent has at least sufficient solubility to diffusetherethrough. The matrix can comprise other materials, including but notlimited to other types of polymers such as polyolefins, polyamides,polyesters, polyvinyl alcohol or acetate, ethylene-vinyl acetatecopolymers, polysaccharides such as cellulose or chitin, or the like,provided the material is biocompatible. Accordingly, selection of amaterial for the matrix can be made at least in part based on the agentselected for the particular application intended, such that a sufficientdegree of solubility of the agent in the matrix can be achieved for atherapeutic level of the agent in the target tissue can be maintainedover a period of time.

Other substances, such as release rate modifying substances such assurfactants, dispersants, fillers, other polymers and oligomers, and thelike, can be included with the matrix in the core.

The substantially impermeable sheath prevents the diffusion of the agenttherethrough. Accordingly, the agent diffuses into surrounding bodyfluids, tissues, etc. largely via that portion of the core that is notcovered by the sheath. The rate of diffusion of the agent into thesurrounding body fluids, tissues, etc. is governed at least in part bythe rate of diffusion of the agent through the matrix. Once a moleculeof the agent reaches the exposed surface of the composite in contactwith the environment, it can diffuse into the surrounding fluid ortissue. In certain embodiments, the therapeutic agent can initially bereleased into a tissue structure adjacent to the target, for exampleinto a punctum of a patient located near the target ocular tissues, fromwhere it can diffuse to the site of action.

In various embodiments, the agent can be soluble or substantiallyinsoluble in the polymeric matrix material. In embodiments wherein theagent is soluble at the concentration used in the polymeric matrixmaterial, the drug core comprises a homogeneous composite wherein theagent is dispersed at a molecular level within the polymeric matrixmaterial. For example, a highly lipophilic agent such as ethynodioldiacetate can dissolve at significant concentrations in siliconepolymer, such that a core can be a homogeneous dispersion of the agentin the matrix at the molecular level. For example, cyclosporine, acyclic peptide analog, can dissolve in significant concentrations inpolyurethane, a polymer that contains linkages resembling amide bonds.When a homogeneous dispersion of the agent in the matrix is present, therate of release of the agent from the exposed surface of the core intothe body fluid or tissue can be controlled by the rate of diffusion ortransport of the agent through the matrix. In embodiments wherein theagent is soluble in the polymeric matrix material, the rate of releaseof the agent into the body tissue or fluid can be determined at least inpart by the concentration of the agent dissolved in the matrix of thecore. In various embodiments, the concentration of therapeutic agentdissolved in the matrix can be a saturation concentration The kineticsof such release can be zero order, first order, or a fractional orderbetween zero and first orders.

In embodiments wherein the agent is only partially or sparingly solubleor insoluble in the matrix at the concentration used, the core comprisesa heterogeneous composition wherein the drug substance is dispersed assolid or liquid inclusions throughout the polymeric matrix material.Where some solubility, however slight, exists, a certain amount of thedrug will be dissolved in the matrix. In various embodiments, theinclusions can range in size from about 0.1 μm to about 100 μm. Wheninclusions of the agent in the matrix are present, the agent may be atleast slightly soluble in the matrix to enable at least some diffusionof the agent from an inclusion to an exposed surface of the drug coresuch that the agent can further diffuse into body fluid or tissue, forexample, the agent can diffuse into tear fluid. When the agent isinsoluble in the matrix, the agent will form domains or inclusions as aseparate phase within the matrix that may cooperate to enablemicrochannels for transport of drug to the matrix surface. In variousembodiments, the agent can be transported via channels or pores in thematrix, which can be permeated by the body fluid. In variousembodiments, the agent can be transported through pores or channelspresent in the matrix.

The agent is present in the core, dispersed in the matrix, in aconcentration. The concentration is a concentration of the agent withina macroscopic portion of the matrix-agent core, that is controlled to besimilar from sample to sample of the core. A similar concentration ofthe agent in a macroscopic portion of the core can vary, but only withinlimits, relative to that in any other equal macroscopic portion of thecore. The term does not relate to concentrations at the molecular level,where domains or inclusions of the agent in concentrated form may bepresent, but rather refers to bulk concentrations of the agent involumes of the core that are greater than at least about 0.1 mm³, forexample, a cubic sample of core about 100 μm on a side, or a 0.1 mmthick slice of a core with cross-sectional area of about 1 mm². Theconcentration can vary within no greater than about 30%, or no greaterthan about 20%, or no greater than about 10%, or no greater than about5%.

In various embodiments, the inclusions can have an average diameter ofless than about 20 μm, or less than about 15 μm, or less than about 10μm. The distribution of diameters of the inclusions can be monodisperse,that is, relatively tightly grouped around the average diameter. If thedistribution of inclusion diameters is a normal or near-normaldistribution, and the monodispersity can be expressed in terms of astandard deviation, a standard deviation of diameters of the inclusionscan be less than about 8 or less than about 6 μm, or less than about 4μm.

Although it is not intended to be a limitation of the invention, thefactors controlling the rate of release of the agent from the matrix tothe patient, such as the release of an ocular drug into tear liquid, arebelieved to be complex and dependent on many variables. For example, adrug and a matrix material may together define a saturationconcentration of the drug in that matrix. For some drug-matrixcombinations, high concentrations of the drug can dissolve in thematrix. For others, a saturation concentration is lower. For stillothers, no solubility exists, and separate domain phases often managerate of release. Another possible factor is the rate of mass transferfrom inclusions to the surface of the matrix. Yet another possiblefactor is the rate of diffusion of the agent from the matrix into a bodyfluid, such as tear liquid.

A rate of release of the therapeutic agent at therapeutic quantities canbe determined at least in part by a concentration of therapeutic agentin the matrix of the drug core. The therapeutic agent can be capable ofsufficiently dissolving into the matrix from the inclusions, if present,so as to maintain the concentration of therapeutic agent dissolved inthe matrix such that the rate of release is within a therapeutic windowfor the extended period. This can lead to a desirable zero order rate ofrelease of the agent, as substantial reservoirs of the agent are presentin the inclusions, while the limited solubility of the agent in thematrix is rate-determining in bringing the agent to the exposed surfaceof the core, where it can be released in tear fluids or other media. Inembodiments wherein the agent is insoluble and forms inclusions in thematrix material, the rate of release of the agent into the body tissueor fluid can be determined at least in part by the concentration of theagent as it diffuses from the inclusions through separate domains in thematrix material to the point of exposure to the body tissue or fluid.

In various embodiment, the matrix includes a release rate varyingmaterial in a quantity sufficient to release the therapeutic agent fromthe drug core at the therapeutic quantities for an extended period whenimplanted for use. The release rate modifying material can include aninert filler material, a salt, a surfactant, a dispersant, a secondpolymer, an oligomer, or a combination thereof. For example, the corecan include a surfactant or a dispersant material, or a filler, anoligomer, another polymer, or the like, in addition to the one or moredrugs and the polymeric matrix material. Examples include polymers suchas polyethyleneglycols (PEGs), sodium alginate, low molecular weightsilicones or polyurethanes, etc. Non-polymeric additives can includehydrophilic solvents such as ethylene glycol or glycerol.

In various embodiments, the core comprises from about 5% to about 50% ofthe drug. Depending on the drug, and the rate of release of the drugfrom the polymer selected for the matrix, the concentration can controlthe period of time over which therapeutic quantities of the drug arereleased into body fluid, such as tear liquid.

In various embodiments, as discussed above, the core can include two ormore drugs. In certain embodiments, both drugs are substantially solublein the matrix material. In other embodiments, a first drug issubstantially soluble in the matrix material and a second drug formsinclusions within the matrix material. In some embodiments, the implantcomprise a single drug core with two therapeutic agents mixed within amatrix. In other embodiments, the implant comprise two drug cores, eachwith a single therapeutic agent.

In some embodiments, the second drug can be a counteractive agent toavoid a side effect of the first therapeutic agent. In one example, thefirst drug can be a cycloplegic drug, i.e., one that blocksaccommodation (focusing) of the eye, e.g., atropine or scopolamine, andthe second therapeutic agent cab be at least one of an anti-glaucomadrug or a miotic drug, selected to reduce the known glaucoma-inducingside effect of cycloplegic drugs or to cause pupil contractioncounteracting the known mydriatic effects of atropine or scopolamine.The anti-glaucoma drug may comprise at least one of a sympathomimetic, aparasympathomimetic, a beta blocking agent, a carbonic anhydraseinhibitor, or prostaglandin analogue. In another example, the firsttherapeutic agent may be a steroid and the second therapeutic agent maybe an antibiotic, wherein the steroids compromise the immune response,but the antibiotics provides protection against infection. In anotherexample, the first therapeutic agent may be pilocarpine and the secondtherapeutic agent may be non-steroidal anti-inflammatory drug (NSAID).An analgesic may be a good compliment for the treatment.

In specific embodiments, the core insert comprises a single drug-matrixcomposite having two drugs contained therein. In other embodiments, thecore insert comprises two separate drug-matrix composites (“subcores” orfirst and second cores), disposed adjacent to each other within thesheath. The two separate composites can be disposed in a concentricspatial configuration, in a sector configuration, or otherwise, providedthat exposed surfaces of both composites are exposed to body tissue orfluid when disposed within the body tissue, cavity, or duct of thepatient.

In some embodiments the therapeutic agents can be released with aprofile that corresponds to a kinetic order of therapeutic agentsrelease and the order can be within a range from about zero to aboutone. In specific embodiments, the range is from about zero to about onehalf, for example from about zero to about one quarter. The therapeuticagents may be released with a profile that corresponds to a kineticorder of therapeutic agents release and the order is within a range fromabout zero to about one half for at least about a month after thestructure is inserted, for example the order can be within the range atleast about 3 months after the structure is inserted.

In various embodiments, the invention provides a filled precursor sheathadapted for manufacture of a plurality of drug inserts therefrom bydivision of the filled precursor sheath, each drug insert being adaptedfor disposition within a respective implant, the implant being adaptedfor disposition within or adjacent to an eye of a patient, for providingsustained release of a therapeutic agent to the eye or surroundingtissues or both. The filled precursor sheath comprises a precursorsheath body and a precursor drug core contained therewithin, theprecursor drug core comprising a therapeutic agent and a matrix whereinthe matrix comprises a polymer and a therapeutic agent. In the precursordrug cores, an amount of the therapeutic agent in a volumetric portionof the precursor drug core is similar to an amount of the therapeuticagent in any other equal volumetric portion of the precursor drug core.The precursor sheath body is substantially impermeable to the agent.Each of the plurality of inserts divided therefrom is adapted to releasethe agent to the eye or surrounding tissues, or both, when in contactwith tear liquid. A respective sheath body of each of the plurality ofinserts divided from the filled precursor sheath is disposed over aportion of a respective drug core of each of the plurality of inserts toinhibit release of the agent from said portion and so as to define atleast one exposed surface of the drug core adapted to release the agentto the eye or surrounding tissues, or both, when the insert is disposedin an implant and the implant is inserted into the patient. For example,an amount of the therapeutic agent in a volumetric portion of theprecursor drug core can vary from an amount of the therapeutic agent inany other equal volumetric portion of the precursor drug core by nogreater than about 30%. For example, an amount of the therapeutic agentin a volumetric portion of the precursor drug core can vary from anamount of the therapeutic agent in any other equal volumetric portion ofthe precursor drug core by no greater than about 20%. For example, anamount of the therapeutic agent in a volumetric portion of the precursordrug core can vary from an amount of the therapeutic agent in any otherequal volumetric portion of the precursor drug core by no greater thanabout 10%. For example, an amount of the therapeutic agent in avolumetric portion of the precursor drug core can vary from an amount ofthe therapeutic agent in any other equal volumetric portion of theprecursor drug core by no greater than about 5%.

In various embodiments, the filled precursor sheath can be adapted toprovide any of the above-discussed drug inserts by division of thefilled precursor sheath. In various embodiments, the precursor sheathcan be divided by cutting with a blade or with a laser, or the like.

In various embodiments, the invention provides an implant body fordisposition in or adjacent to an eye of a patient for release of atherapeutic agent over a period of time to the eye or surroundingtissues, or both. The implant body comprises a channel therein adaptedto receive a drug insert such that an exposed surface of the insert willbe exposed to tear liquid when the insert is disposed within the implantand when the implant is disposed in or adjacent to the eye. The druginsert comprises a sheath body that is substantially impermeable to theagent, containing therewithin a drug core comprising a therapeutic agentand a matrix comprising a polymer, wherein an amount of the therapeuticagent in a volumetric portion of the drug core is similar to an amountof the therapeutic agent in any other equal volumetric portion of thedrug core. The implant body comprises a biocompatible material and beingadapted to be retained within or adjacent to the eye for a period oftime. For example, the amount of the therapeutic agent in a volumetricportion of the drug core can vary from the amount of the therapeuticagent in any other equal volumetric portion of the drug core by nogreater than about 30%. For example, the amount of the therapeutic agentin a volumetric portion of the drug core can vary from the amount of thetherapeutic agent in any other equal volumetric portion of the drug coreby no greater than about 20%. For example, the amount of the therapeuticagent in a volumetric portion of the drug core can vary from the amountof the therapeutic agent in any other equal volumetric portion of thedrug core by no greater than about 10%. For example, the amount of thetherapeutic agent in a volumetric portion of the drug core can vary fromthe amount of the therapeutic agent in any other equal volumetricportion of the drug core by no greater than about 5%.

In various embodiments, an exposed surface of the drug core containedwithin the implant is capable of releasing the therapeutic quantitiesinto at least one of a sclera, a cornea or a vitreous when disposed inor adjacent to the eye of the patient. For example, the implant can be apunctal plug adapted for disposition within a punctum of a patient forrelease of the agent into tear liquid.

In various embodiments of the inventive methods described above, themixture can further comprise a solvent in which the matrix precursor andthe agent are soluble, and curing can comprise at least partial removalof the solvent following injection into the sheath body or precursorsheath body respectively. Curing can involve heating, vacuum treatment,or both. The solvent can be a hydrocarbon, an ester, a halocarbon, analcohol, an amide, or a combination thereof. For example, when the agentis cyclosporine, the solvent can be a halocarbon.

In various embodiments, curing the mixture can comprise heating themixture to a temperature, at a relative humidity, for a period of time.For example, the temperature can include a range from about 20 degreesC. to about 100 degrees C., the relative humidity can include a rangefrom about 40% to about 100%, and the period of time can include a rangefrom about 1 minute to about 48 hours. More specifically, thetemperature can be at least about 40° C., the relative humidity can beat least about 80%, or both. In various embodiments, curing can includea step of polymerization or cross-linking, or both, of the matrix, thematrix precursor, or both. For example, polymerization or cross-linking,or both, can be carried out in the presence of a catalyst. For instance,the catalyst can be a tin compound or a platinum compound, such as aplatinum with vinyl hydride catalyst system or a tin with alkoxycatalyst system.

In various embodiments, the mixture can be prepared by a methodcomprising sonication. The matrix precursor and the agent can be mixedto provide a thoroughly dispersed emulsion-like composite, wherein theagent, if insoluble or slightly soluble in the matrix precursor, isdispersed in small particles or droplets.

In various embodiments, the step of injecting the mixture into thesheath can be carried out under a pressure of at least about 40 psi. Themixture can be injected such that the sheath body or precursor sheathbody, respectively, is filled at a rate of no greater than about 0.5cm/sec.

The injection or extrusion of the mixture including the agent and thematrix precursor or matrix can be carried out at room temperature (20°C.), or above room temperature, or can be carried out at subambienttemperatures of less than 20° C. For example, the injection can becarried out wherein the subambient temperature comprises a temperatureof about −50° C. to about 20° C., or wherein the subambient temperaturecomprises a temperature of about −20° C. to about 0° C.

As discussed below, FIGS. 15 and 16 provide graphical evidence of theadvantages of subambient extrusion, both in terms of uniformity ofinclusion diameter, and in terms of uniformity of distribution of thetherapeutic agent throughout the length of a filled precursor sheath.FIG. 15 shows electron micrographs of cryogenically section portions ofa drug core wherein the extrusion was carried out at varioustemperatures. As can be seen, the average diameter of the includeddroplets of latanoprost is smaller when the extrusion is carried out at0° C. or −25° C. than when the extrusion is carried out at 25° C. or at40° C.

In a parallel experiment, described in Examples 12 and 13, averageinclusion diameters; and diameter size distributions, were determinedfor extrusions carried out at room temperature and at −5° C. for alatanoprost-silicone mixture:

Cold extrusion (−5° C.): 0.006±0.002 mm (n=40 inclusion),

Room temp (22° C.): 0.019±0.019 mm (n=40 inclusion), showing that thecold extrusion technique produced inclusions of smaller average diameterand of more uniform size than when the extrusion was carried out atambient temperature.

FIG. 16 shows graphically the content of latanoprost in a 10 cmprecursor sheath filled with the latanoprost-silicone mixture, asdiscussed in Examples 12 and 13. As can be seen, cold extrusion at −25°C. and 0° C. (squares) unexpectedly produced a more uniform distributionof therapeutic agent latanoprost in the silicone matrix, after curing,along the entire length of the 10 cm precursor sheath, which wassubsequently divided into 1 mm sections, and the latanoprost content ofeach sections (drug insert) determined Extrusions carried out at roomtemperature (circles) and at 40° C. (triangles) were significantly morevariable. The results are significant in terms of manufacturingmedically useful devices, as it is desirable to maintain a uniformcontent of the therapeutic agent among a plurality of drug insertsmanufactured by this method.

In various embodiments, each drug insert can be sealed at one endthereof, the second end thereby providing the exposed surface forrelease of the agent when the insert is disposed within an implant andinserted into a patient. Each drug insert can be sealed at one endthereof using a UV-curable adhesive, a cyanoacrylate, an epoxy, bypinching, with a heat weld, or with a cap. When a UV-curable adhesive isused, curing is carried out by irradiation with UV light.

In various embodiments, the inventive methods further comprise, aftersealing one end thereof, inserting each drug insert into a channel of arespective implant body adapted to receive the insert therein.

In various embodiments, when the drug core comprises two drug cores, afirst drug core comprising a first agent and a first matrix, and asecond drug core comprising a second agent and a second matrix, whereinthe first agent and the second agent are different, and wherein thefirst matrix and the second matrix are either the same or differ fromeach other, the implant body comprising an aperture adapted to receivethe drug insert comprising the first and the second drug cores, themethod can further comprise disposing the drug cores within the insertprior to disposing the insert comprising the drug cores within theaperture of the implant body.

In various embodiments, where the therapeutic agent comprisescyclosporine or olopatadine, a prodrug or a derivative of cyclosporineor olopatadine or any combination thereof, the matrix includespolyurethane, and a weight ratio of the cyclosporine or the olopatadineor the cyclosporine prodrug or derivative, or the olopatadine prodrug orderivative, or the combination thereof, to the polyurethane polymer orcopolymer is about 1 wt % to about 70 wt %, the method can includeforming the mixture by melting and mixing the polyurethane polymer orcopolymer and the therapeutic agent. The therapeutic agent can be inmolten form in the mixture, or can be in solid form in the mixture.

In some embodiments, the matrix comprises an inert filler material mixedwith the therapeutic agent such that the exposed surface releases thetherapeutic agent at therapeutic quantities for a sustained period oftime.

In some embodiments, a salt is mixed with the matrix precursor such thatthe exposed surface of the matrix, after curing, releases thetherapeutic agent at therapeutic quantities for a sustained period oftime.

In some embodiments, a surfactant is mixed with the matrix precursorsuch that the exposed surface of the matrix, after curing, releases thetherapeutic agent at therapeutic quantities for a sustained period oftime.

In some embodiments a second polymer or an oligomer is mixed with thematrix precursor, and after curing to form the matrix, the presence ofthe second polymer or oligomer can serve to vary the rate of release ofthe therapeutic agent.

Various embodiments of the invention provide a punctum plug forinsertion into a punctal canal of a patient, the plug comprising a drugcore having a distal end and a proximal end, at least the distal end ofthe drug core having a cross section suitable for insertion through apunctum, the drug core comprising a polyurethane polymer or copolymercomprising a therapeutic agent deliverable into the eye or surroundingtissues; and a substantially impermeable sheath disposed over a portionof the drug core to define at least one exposed surface of the drugcore, at least one exposed surface of the drug core being located nearthe proximal end to contact a tear or tear film fluid of a patient andrelease the therapeutic agent at therapeutic levels over a sustainedperiod when the plug is implanted for use within the punctal canal ofthe patient. The inventive plug includes a core, in which thetherapeutic agent is contained, that is formed from a polyurethanepolymer or copolymer. The polyurethane polymer or copolymer of the corecan be an aliphatic polyurethane, an aromatic polyurethane, apolyurethane hydrogel-forming material, a hydrophilic polyurethane, or acombination thereof. For example, the core can be formed of thepolyurethane hydrogel-forming material TG-500 or TG-2000 aliphatic,polyether based thermoplastic polyurethanes capable of forminghydrogels. Such hydrogel-forming polymers can absorb greater than 100 wt%, for example up to 500-2000 wt % of water, and consequently swell inphysical dimensions. Alternatively, the core can be formed of ahydrophilic polyurethane such as Pursil, which swells much less, to theextent of about 20-100%, upon contact with an aqueous medium. Otherexamples include Lubrizol products including Tecophilic grades such asHP-60D20, HP-60D35, HP-60D60, or HP-93A100.

In various embodiments, the therapeutic agent can comprise cyclosporine,or a prodrug or a derivative of cyclosporine. Cyclosporine, as iswell-known in the art, is an immunomodulator, and can be used in thetreatment of dry eye and inflammations of the eye, such as thoseresulting from an allergic response. The weight ratio of thecyclosporine or the cyclosporine prodrug or derivative, respectively, tothe polyurethane polymer or copolymer can be about 1 wt % up to as highas about 70 wt %, or even greater. The rate of the release of thecyclosporine, or its prodrug or derivative, can be controlled byselection of the specific kind of polyurethane for the core and bymodulating the polarity (hydrophobicity/hydrophilicity) of thetherapeutic agent. Cyclosporine is a rather hydrophobic compound, butcan be rendered more hydrophilic by incorporation of functional groups,such as groups that can be cleaved in vivo by endogenous enzymes likeesterases, wherein the functional groups incorporated have hydrophilicmoieties included.

In various embodiments, the therapeutic agent can be olopatidine, or aprodrug or a derivative of olopatidine. For instance, the agent can beolopatidine hydrochloride, also known as patanol. Used to treat allergicconjunctivitis (itching eyes), olopatadine inhibits the release ofhistamine from mast cells. It is a relatively selective histamine H1antagonist that inhibits the in vivo and in vitro type 1 immediatehypersensitivity reaction including inhibition of histamine inducedeffects on human conjunctival epithelial cells.

The plug further includes a substantially impermeable sheath, to limitthe zone or region of release of the therapeutic agent to the at leastone exposed surface of the drug core, disposed immediately adjacent tothe punctum of the eye such that the therapeutic agent is readilycontacted by tear fluid and can thus diffuse over the surface of theeye. For example, cyclosporine can be released into the tear fluid toassist in treatment of the eye for dryness or for inflammation, such ascaused by an allergic reaction. The sheath can also be adapted toprovide a second exposed surface of the drug core is located near thedistal end of the plug to release the therapeutic agent into the punctalcanal, if such is desired. For example, a second therapeutic agent canbe included, such as an antibiotic for treatment of infections of thepunctal canal.

The sheath can be of sufficient elasticity or flexibility that when thecore is adapted to swell when in contact with an aqueous medium, such aswhen the core is constructed of a hydrophilic or hydrogel-formingpolyurethane polymer or copolymer, that the sheath can expand inresponse to the swelling of the hydrophilic or hydrogel-formingpolyurethane polymer or copolymer. The swelling is adapted to assist inretaining the plug within the punctal canal.

The core can further contain a second bioactive agent, such as arelisted below, such as for treatment of a secondary condition or toassist in treatment of the condition, for example, for whichadministration of cyclosporine or olopatidine, or both, is medicallyindicated.

The lacrimal implant can be any suitable shape adapted for insertioninto the punctal canal of the eye. For example, the implant can besubstantially cylindrical at the time of insertion into the canal, priorto swelling of any hydrogel-forming core of the plug. Or, the implantcan be of a conical shape, or can be bent in the form of an “L”, or canhave any other shape which can be disposed within the punctal canal of apatient's eye such that the therapeutic agent can be released from thecore into the tear fluid bathing the eye. Accordingly, the core of theimplant, when the implant is disposed within the punctal canal, hasaccess to the opening of the punctum such that the agent can diffuseinto the tear fluid and thereby bathe the eye surface. In variousembodiments, the core has access to the interior of the punctal canalfor release of the agent thereto.

For example, the implant can be a shape termed the “bent-design” asdisclosed in a patent application filed concurrently with thisapplication. Or, the implant can be a design referred to as the“H-design”, as disclosed in a patent application filed concurrently withthis application. Or, the implant can be what is termed the “skeleton”design as disclosed in a patent application filed concurrently with thisapplication.

In various embodiments, a method of manufacture of the inventiveimplant, comprising melting and mixing the polyurethane polymer orcopolymer and adding the therapeutic agent to form a mixed melt, then,either casting the mixed melt within the sheath, or, casting the mixedmelt to form the core, then disposing the sheath around the core, isprovided.

The polyurethane selected to form the core of the implant can bethermoplastic such that the implant can be manufactured by a meltextrusion or casting process. For example, a melt of the corepolyurethane can be prepared and the therapeutic agent can beincorporated therein. In various embodiments, the agent can melt at atemperature around the melting point of a suitable polyurethane polymeror copolymer, and the agent can itself be incorporated in a moltenstate, provided the melting point is at a temperature at or below thedecomposition temperature of the polyurethane, and the melting point ofthe polyurethane is below a temperature at which the agent undergoessignificant thermal decomposition. For example, cyclosporine melts atabout 135° C., while TG-500 melts at about 170° C. and TG-2000 melts atabout 115° C. Thus, a mixed melt can be prepared at about 135° C., orhigher with TG-2000 wherein both the cyclosporine and the polyurethanecore material are both in a molten state. A higher melting material likeTG-500 can be used when the cyclosporine is stable for the time periodit is held at the elevated temperate in the process used.

In various embodiments, the agent does not melt in the moltenpolyurethane, but is dispersed as a solid, which in be in the form of afine powder, such as a microparticulate form. For example, olopatidine,which melts in excess of 200° C., can be dispersed in solid form in amelt of a polyurethane The polyurethane melt containing the solid agentis then cast, optionally within a sheath, to provide the inventive plug.

Thus, melt mixing processes can be cast to form an inventive implant.For example, the mixed melt can be cast into a mold already lined with ahigher melting sheath material, which can be a polyurethane that is notsubstantially permeable to diffusion of the cyclosporine. In this waythe sheathed implant can be prepared. Alternatively, the core can becase in a mold, then the sheath material coated or cast on the surfaceof the implant, except for regions where the core material is to be leftexposed. Or, the sheath material can be cast to cover the entireimplant, then a portion removed to expose the core material in at leastone location near the proximal end, where the cyclosporine can readilycome into contact with tear fluid and thereby diffuse into the eye.

In various embodiments, a method of manufacture of the inventiveimplant, comprising dissolving the polyurethane polymer or copolymer andmixing in the therapeutic agent in a solvent to form a mixed solution,then, either casting the mixed solution within the sheath, then removingthe solvent, or, casting the mixed solution to form the core, thenremoving the solvent, then disposing the sheath around the core, isprovided.

The polyurethane selected to form the core of the implant can be solublein an organic solvent, such as dichloromethane or tetrahydrofuran. Manytherapeutic agent, for example, cyclosporine, are also soluble in manyorganic solvents, including dichloromethane or tetrahydrofuran. In thisway a mixed solution can be prepared. This solution can then be used tocast the core of the implant, with removal of the solvent. The solventcan be removed by evaporation, which can be carried out under ambientconditions, or can involve the application of heat, reduced atmosphericpressure, or both. After removal of the solvent, the sheath can becoated or cast around the core, either leaving an exposed section of thecore, or removing a portion of the sheath to provide an exposed section.

In various embodiments, a method of manufacture of an inventive implantcomprises dissolving the polyurethane polymer or copolymer in a solvent,then adding a therapeutic agent in solid form, the agent beingsubstantially insoluble in the solvent, then removing the solvent tocast the core. The solid form of the agent can be a fine powder, such asa microparticulate form, to provide for a favorable surface area/massratio. In various embodiments the implant comprises a dispersion of asolid form of the agent in the polyurethane polymer or copolymer.

The polyurethane polymer or copolymer making up the core can be analiphatic polyurethane, an aromatic polyurethane, a polyurethanehydrogel-forming material, a hydrophilic polyurethane, or a combinationthereof. The particular polyurethane used for the therapeutic agent canbe selected to control the release profile of the agent over time.

The inventive implant can be used to treat a malcondition of the eye orof surrounding tissue. For example, the implant incorporatingcyclosporine or olopatidine, or both, can be used to treat an eyemalcondition involving dry eye or eye inflammation. The therapeuticagent can be released into the eye, as well as into surrounding tissuesuch as the interior of the punctal canal, over a period of time. Theperiod of time can be about 1 week to about 6 months. When a swellingpolyurethane is used, the swelling of the implant can be used to securethe plug within the punctal canal for the full time period over whichthe drug is adapted to be released.

In various embodiments, the invention provides a drug insert made by amethod of the invention.

In various embodiments, the invention provides a method of treating amalcondition in a patient in need thereof, comprising disposing animplant comprising a drug insert of the invention, or a drug core of theinvention, or a drug core obtained by division of a filled precursorsheath of the invention, or a drug implant of the invention, or a druginsert prepared by the method of the invention, wherein the therapeuticagent is adapted to treat the malcondition, in or adjacent to an eye ofthe patient such that the drug is released into a body tissue or fluid.

In various embodiments, the invention provides the use of a drug insertof the invention, or a drug core of the invention, or a drug coreobtained by division of a filled precursor sheath of the invention, or adrug implant of the invention, or a drug insert prepared by the methodof the invention, in the manufacture of an implant adapted for treatmentof a malcondition in a patient in need thereof.

In various embodiments, the invention provides a drug insert adapted fordisposition within an punctal plug for providing sustained release of alatanoprost to the eye for treatment of glaucoma, the insert comprisinga core and a sheath body partially covering the core, the corecomprising the latanoprost and a matrix wherein the matrix comprises asilicone polymer, the latanoprost being dispersed within the silicone asdroplets thereof, wherein an amount of the latanoprost in a volumetricportion of the drug core is similar to an amount of the latanoprost inany other equal volumetric portion of the drug core, the sheath bodybeing disposed over a portion of the core to inhibit release of thelatanoprost from said portion, an exposed surface of the core notcovered by the sheath body being adapted to release the latanoprost tothe eye.

In various embodiments, the invention provides a drug insert adapted fordisposition within an punctal plug for providing sustained release of acyclosporine to the eye for treatment of dry eye or inflammation, theinsert comprising a core and a sheath body partially covering the core,the core comprising the cyclosporine and a matrix wherein the matrixcomprises a polyurethane polymer, the cyclosporine being dissolvedwithin the polyurethane, wherein an amount of the cyclosporine in avolumetric portion of the drug core is similar to an amount of thecyclosporine in any other equal volumetric portion of the drug core, thesheath body being disposed over a portion of the core to inhibit releaseof the cyclosporine from said portion, an exposed surface of the corenot covered by the sheath body being adapted to release the cyclosporineto the eye.

Discussion of the Figures

FIG. 1A shows a top cross sectional view of a sustained release implant100 to treat an optical defect of an eye, according to embodiments ofthe present invention. Implant 100 includes a drug core 110. Drug core110 is an implantable structure that retains a therapeutic agent. Drugcore 110 comprises a matrix 170 that contains inclusions 160 oftherapeutic agent. Inclusions 160 will often comprise a concentratedform of the therapeutic agent, for example a crystalline form of thetherapeutic agent, and the therapeutic agent may over time dissolve intomatrix 170 of drug core 110. Matrix 170 can comprise a silicone matrixor the like, and the mixture of therapeutic agent within matrix 170 canbe non-homogeneous. In many embodiments, the non-homogenous mixturecomprises a silicone matrix portion that is saturated with thetherapeutic agent and an inclusions portion comprising inclusions of thetherapeutic agent, such that the non-homogenous mixture comprises amultiphase non-homogenous mixture. In some embodiments, inclusions 160comprise droplets of an oil of the therapeutic agent, for exampleLatanoprost oil. In some embodiments, inclusions 160 may compriseparticles of the therapeutic agent, for example solid Bimatoprostparticles in crystalline form. In many embodiments, matrix 170encapsulates inclusions 160, and inclusions 160 may comprisemicroparticles have dimensions from about 1 μm to about 100 μm. Theencapsulated inclusions dissolve into the surrounding solid matrix, forexample silicone, that encapsulates the micro particles such that matrix170 is substantially saturated with the therapeutic agent while thetherapeutic agent is released from the core.

Drug core 110 is surrounded by a sheath body 120. Sheath body 120 is canbe substantially impermeable to the therapeutic agent, so that thetherapeutic agent is often released from an exposed surface on an end ofdrug core 110 that is not covered with sheath body 120. A retentionstructure 130 is connected to drug core 110 and sheath body 120.Retention structure 130 is shaped to retain the implant in a hollowtissue structure, for example, a punctum of a canaliculus as describedabove.

An occlusive element 140 is disposed on and around retention structure130. Occlusive element 140 is impermeable to tear flow and occludes thehollow tissue structure and may also serve to protect tissues of thetissue structure fiom retention structure 130 by providing a more benigntissue-engaging surface. Sheath body 120 includes a sheath body portion150 that connects to retention structure 130 to retain sheath body 120and drug core 110. Sheath body portion 150 can include a stop to limitmovement of sheath body 120 and drug core 110. In many embodiments,sheath body portion 150 can be formed with a bulbous tip 150B. Bulboustip 150B can comprise a convex rounded external portion that providesatraumatic entry upon introduction into the canaliculus. In manyembodiments, sheath body portion 150B can be integral with occlusiveelement 140.

FIG. 1B shows a side cross sectional view of the sustained releaseimplant of FIG. 1A. Drug core 110 is cylindrical and shown with acircular cross-section. Sheath body 120 comprises an annular portiondisposed on drug core 110. Retention structure 130 comprises severallongitudinal struts 131. Longitudinal struts 131 are connected togethernear the ends of the retention structure. Although longitudinal strutsare shown, circumferential struts can also be used. Occlusive element140 is supported by and disposed over longitudinal struts 131 ofretention structure 130 and may comprise a radially expandable membraneor the like.

FIG. 1C shows a perspective view of a sustained release implant 102 witha coil retention structure 132, according to an embodiment of thepresent invention. Retention structure 132 comprises a coil and retainsa drug core 112. A lumen, for example channel 112C, may extend throughthe drug core 112 to permit tear flow through the lumen for the deliveryof therapeutic agent for nasal and systemic applications of thetherapeutic agent. In addition or in combination with channel 112C,retention structure 132 and core 112 can be sized to permit tear flowaround the drug core and sheath body while the retention element holdstissue of the canaliculus away from the drug core. Drug core 112 may bepartially covered. The sheath body comprises a first component 122A thatcovers a first end of drug cove 112 and a second component 122B thatcovers a second end of the drug core. An occlusive element can be placedover the retention structure and/or the retention structure can be dipcoated as described above.

FIG. 1D shows a perspective view of a sustained release implant 104 witha retention structure 134 comprising struts, according to an embodimentof the present invention. Retention structure 134 comprises longitudinalstruts and retains a drug core 114. Drug core 114 is covered with asheath body 124 over most of drug core 114. The drug core releasestherapeutic agent through an exposed end and sheath body 124 is annularover most of the drug core as described above. An occlusive element canbe placed over the retention structure or the retention structure can bedip coated as described above. A protrusion that can be engaged with aninstrument, for example a hook, a loop, a suture, or ring 124R, canextend from sheath body 124 to permit removal of the drug core andsheath body together so as to facilitate replacement of the sheath bodyand drug core while the retention structure remains implanted in thecanaliculus. In some embodiments, a protrusion that can be engaged withan instrument comprising hook, a loop, a suture or a ring, can extendfrom retention structure 134 to permit removal of the sustained releaseimplant by removing the retention structure with the protrusion, drugcore and sheath body.

FIG. 1E shows a perspective view of a sustained release implant 106 witha cage retention structure 136, according to an embodiment of thepresent invention. Retention structure 136 comprises several connectedstrands of metal and retains a drug core 116. Drug core 116 is coveredwith a sheath body 126 over most of drug core 116. The drug corereleases therapeutic agent through an exposed end and sheath body 126 isannular over most of the drug core as described above. An occlusiveelement can be placed over the retention structure or the retentionstructure can be dip coated as described above.

FIG. 1F shows a perspective view of a sustained release implantcomprising a core and sheath, according to an embodiment of the presentinvention. Drug core 118 is covered with a sheath body 128 over most ofdrug core 118. The drug core releases therapeutic agent through anexposed end and sheath body 128 is annular over most of the drug core asdescribed above. The rate of therapeutic agent release is controlled bythe surface area of the exposed drug core and materials included withindrug core 118. In many embodiments, the rate of elution of thetherapeutic agent is strongly and substantially related to the exposedsurface area of the drug core and weakly dependent on the concentrationof drug disposed in the inclusions in the drug core. For circularexposed surfaces the rate of elution is strongly dependent on thediameter of the exposed surface, for example the diameter of an exposeddrug core surface near an end of a cylindrical drug core. Such animplant can be implanted in ocular tissues, for example belowconjunctival tissue layer 9 of the eye and either above sclera tissuelayer 8, as shown in FIG. 1F, or only partially within the scleraltissue layer so as not to penetrate the scleral tissue. It should benoted that drug core 118 can be used with any of the retentionstructures and occlusive elements as described herein.

In an embodiment, the drug core is implanted between sclera 8 andconjunctiva 9 without sheath body 128. In this embodiment without thesheath body, the physical characteristics of the drug core can beadjusted to compensate for the increased exposed surface of drug core,for example by reducing the concentration of dissolved therapeutic agentin the drug core matrix as described herein.

FIG. 1G schematically illustrates a sustained release implant 180comprising a flow restricting retention structure 186, a core 182 and asheath 184, according to an embodiment of the present invention. Sheathbody 184 can at least partially cover drug core 182. Drug core 182 maycontain inclusions of the therapeutic agent therein to provide asustained release of the therapeutic agent. Drug core 182 can include anexposed convex surface area 182A. Exposed convex surface area 182A mayprovide an increased surface area to release the therapeutic agent. Anocclusive element 188 can be disposed over retention structure 186 toblock the flow of tear through the canaliculus. In many embodiments,retention structure 186 can be located within occlusive structure 188 toprovide the occlusive element integrated with the retention structure.Flow restricting retention structure 186 and occlusive element 188 canbe sized to block tear flow through the canaliculus.

The cores and sheath bodies described herein can be implanted in avariety of tissues in several ways. Many of the cores and sheathsdescribed herein, in particular the structures described with referenceto FIGS. 2A to 2J can be implanted alone as punctal plugs.Alternatively, many of the cores and sheath bodies described herein cancomprise a drug core, sheath body, and/or the like so as to be implantedwith the retention structures and occlusive elements described herein.

FIG. 2A shows a cross sectional view of a sustained release implant 200with core comprising an enlarged exposed surface area, according to anembodiment of the present invention. A drug core 210 is covered with asheath body 220. Sheath body 220 includes an opening 220A. Opening 220has a diameter that approximates the maximum cross sectional diameter ofdrug core 210. Drug core 210 includes an exposed surface 210E, alsoreferred to as an active surface. Exposed surface 210E includes 3surfaces: an annular surface 210A, a cylindrical surface 210B and an endsurface 210C. Annular surface 210A has an outer diameter thatapproximates the maximum cross sectional diameter of core 210 and aninner diameter that approximates the outer diameter of cylindricalsurface 210B. End surface 210C has a diameter that matches the diameterof cylindrical surface 210B. The surface area of exposed surface 210E isthe sum of the areas of annular surface 210A, cylindrical surface 210Band end surface 210C. The surface area may be increased by the size ofcylindrical surface area 210B that extends longitudinally along an axisof core 210.

FIG. 2B shows a cross sectional view of a sustained release implant 202with a core 212 comprising an enlarged exposed surface area 212A,according to an embodiment of the present invention. A sheath body 222extends over core 212. The treatment agent can be released from the coreas described above. Exposed surface area 212A is approximately conical,can be ellipsoidal or spherical, and extends outward from the sheathbody to increase the exposed surface area of drug core 212.

FIGS. 2C and 2D show perspective and cross sectional views,respectively, of a sustained release implant 204 with a drug core 214comprising a reduced exposed surface area 214A, according to anembodiment of the present invention. Drug core 214 is enclosed within asheath body 224. Sheath body 22 includes an annular end portion 224Athat defines an opening through which drug core 214 extends. Drug core214 includes an exposed surface 214A that releases the therapeuticagent. Exposed surface 214A has a diameter 214D that is less than amaximum dimension, for example a maximum diameter, across drug core 214.

FIG. 2E shows a cross sectional view of a sustained release implant 206with a drug core 216 comprising an enlarged exposed surface area 216Awith castellation extending therefrom, according to an embodiment of thepresent invention. The castellation includes several spaced apartfingers 216F to provide increased surface area of the exposed surface216A. In addition to increased surface area provided by castellation,drug core 216 may also include an indentation 2161. Indentation 2161 mayhave the shape of an inverted cone. Core 216 is covered with a sheathbody 226. Sheath body 226 is open on one end to provide an exposedsurface 216A on drug core 216. Sheath body 226 also includes fingers andhas a castellation pattern that matches core 216.

FIG. 2F shows a perspective view of a sustained release implant 250comprising a core with folds, according to an embodiment of the presentinvention. Implant 250 includes a core 260 and a sheath body 270. Core260 has an exposed surface 260A on the end of the core that permits drugmigration to the surrounding tear or tear film fluid. Core 260 alsoincludes folds 260F. Folds 260F increase the surface area of core thatis exposed to the surrounding fluid tear or tear film fluid. With thisincrease in exposed surface area, folds 260F increase migration of thetherapeutic agent from core 260 into the tear or tear film fluid andtarget treatment area. Folds 260F are formed so that a channel 260C isformed in core 260. Channel 260C connects to the end of the core to anopening in exposed surface 260A and provides for the migration oftreatment agent. Thus, the total exposed surface area of core 260includes exposed surface 260A that is directly exposed to the tear ortear film fluid and the surfaces of folds 260F that are exposed to thetear or tear film fluids via connection of channel 260C with exposedsurface 260A and the tear or tear film fluid.

FIG. 2G shows a perspective view of a sustained release implant with acore comprising a channel with an internal surface, according to anembodiment of the present invention. Implant 252 includes a core 262 andsheath body 272. Core 262 has an exposed surface 262A on the end of thecore that permits drug migration to the surrounding tear or tear filmfluid. Core 262 also includes a channel 262C. Channel 262C increases thesurface area of the channel with an internal surface 262P formed on theinside of the channel against the core. In some embodiment, the internalexposed surface may also be porous. Channel 262C extends to the end ofthe core near exposed surface 262A of the core. The surface area of corethat is exposed to the surrounding tear or tear film fluid can includethe inside of core 262 that is exposed to channel 262C. This increase inexposed surface area can increase migration of the therapeutic agentfrom core 262 into the tear or tear film fluid and target treatmentarea. Thus, the total exposed surface area of core 262 can includeexposed surface 260A that is directly exposed to the tear or tear filmfluid and internal surface 262P that is exposed to the tear or tear filmfluids via connection of channel 262C with exposed surface 262A and thetear or tear film fluid.

FIG. 2H shows a perspective view of a sustained release implant 254 witha core 264 comprising channels to increase drug migration, according toan embodiment of the invention. Implant 254 includes core 264 and sheathbody 274. Exposed surface 264A is located on the end of core 264,although the exposed surface can be positioned at other locations.Exposed surface 264 A permits drug migration to the surrounding tear ortear film fluid. Core 264 also includes channels 264C. Channels 264Cextend to exposed surface 264. Channels 264C are large enough that tearor tear film fluid can enter the channels and therefore increase thesurface area of core 264 that is in contact with tear or tear filmfluid. The surface area of the core that is exposed to the surroundingfluid tear or tear film fluid includes the inner surfaces 264P of core262 that define channels 264C. With this increase in exposed surfacearea, channels 264C increase migration of the therapeutic agent fromcore 264 into the tear or tear film fluid and target treatment area.Thus, the total exposed surface area of core 264 includes exposedsurface 264A that is directly exposed to the tear or tear film fluid andinternal surface 264P that is exposed to the tear or tear film fluidsvia connection of channels 262C with exposed surface 264A and the tearor tear film fluid.

FIG. 2I shows a perspective view of a sustained release implant 256 witha drug core 266 comprising a convex exposed surface 266A, according toan embodiment of the present invention. Drug core 266 is partiallycovered with a sheath body 276 that extends at least partially over drugcore 266 to define convex exposed surface 266A. Sheath body 276comprises a shaft portion 276S. Convex exposed surface 266A provides anincreased exposed surface area above the sheath body. A cross sectionalarea of convex exposed surface 266A is larger than a cross sectionalarea of shaft portion 276S of sheath body 276. In addition to the largercross sectional area, convex exposed surface 266A has a larger surfacearea due to the convex shape which extends outward from the core. Sheathbody 276 comprises several fingers 276F that support drug core 266 inthe sheath body and provide support to the drug core to hold drug core266 in place in sheath body 276. Fingers 276F are spaced apart to permitdrug migration from the core to the tear or tear film fluid between thefingers. Protrusions 276P extend outward on sheath body 276. Protrusions276P can be pressed inward to eject drug core 266 from sheath body 276.Drug core 266 can be replaced with another drug core after anappropriate time, for example after drug core 266 has released most ofthe therapeutic agent.

FIG. 2J shows a side view of a sustained release implant 258 with a core268 comprising an exposed surface area with several soft brush-likemembers 268F, according to an embodiment of the present invention. Drugcore 268 is partially covered with a sheath body 278 that extends atleast partially over drug core 268 to define exposed surface 268A.Sheath body 278 comprises a shaft portion 278S. Soft brush-like members268F extend outward from drug core 268 and provide an increased exposedsurface area to drug core 268. Soft brush-like members 268F are alsosoft and resilient and easily deflected such that these members do notcause irritation to neighboring tissue. Although drug core 268 can bemade of many materials as explained above, silicone is a suitablematerial for the manufacture of drug core 268 also comprises soft brushlike members 268F. Exposed surface 268A of drug core 268 also includesan indentation 2681 such that at least a portion of exposed surface 268Ais concave.

FIG. 2K shows a side view of a sustained release implant 259 with a drugcore 269 comprising a convex exposed surface 269A, according to anembodiment of the present invention. Drug core 269 is partially coveredwith a sheath body 279 that extends at least partially over drug core269 to define convex exposed surface 269A. Sheath body 279 comprises ashaft portion 279S. Convex exposed surface 269 provides an increasedexposed surface area above the sheath body. A cross sectional area ofconvex exposed surface 269A is larger than a cross sectional area ofshaft portion 279S of sheath body 279. In addition to the larger crosssectional area, convex exposed surface 269A has a larger surface areadue to the convex shape that extends outward on the core. A retentionstructure 289 can be attached to sheath body 279. Retention structure289 can comprise any of the retention structures as describe herein, forexample a coil comprising a super elastic shape memory alloy such asNitinol™. Retention structure 289 can be dip coated to make retentionstructure 289 biocompatible.

FIG. 2L shows a side view of a sustained release implant 230 with a drugcore 232 comprising a concave indented surface 232A to increase exposedsurface area of the core, according to an embodiment of the presentinvention. A sheath body 234 extends at least partially over drug core232. Concave indented surface 232A is formed on an exposed end of drugcore 232 to provide an increased exposed surface area of the drug core.

FIG. 2M shows a side view of a sustained release implant 240 with a drugcore 242 comprising a concave surface 242A with a channel 242C formedtherein to increase an exposed surface area of the core, according to anembodiment of the present invention. A sheath body 244 extends at leastpartially over drug core 242. Concave indented surface 242A is formed onan exposed end of drug core 232 to provide an increased exposed surfacearea of the drug core. Channel 242C formed in drug core 242 to providean increased exposed surface area of the drug core. Channel 242C canextend to concave indented surface 242A such that channel 242C andprovide an increase in surface area of the core exposed to the tear ortear film.

Referring now to FIGS. 3A and 3B an implant, for example a punctal plug300, is shown which comprises a silicone body 310, a drug core 320 and aretention structures 330, according to embodiments of the presentinvention. Body 310 comprises a proximal channel 314 sized to receivedrug core insert 320. Body 310 comprises a distal channel 318. Distalchannel 318 can be sized to receive a hydrogel rod 332. A partition 319may separate the proximal channel from the distal channel. A filament334 can be embedded in body 310 and wrapped around hydrogel rod 332 toaffix hydrogel rod 332 to body 310.

Drug core insert 320 may comprise a sheath 322, which is substantiallyimpermeable to the drug so as to direct the drug toward an exposedsurface 326 of the drug core. Drug core 320 may comprises a siliconematrix 328 with inclusions 324 of the drug encapsulated therein. Thedrug core insert and manufacture of the drug core insert are describedin U.S. application Ser. Nos. 11/695,537 and 11/695,545, the fulldisclosures of which are incorporated herein by reference. In someembodiments, body 310 may comprise an annular rim 315 near exposedsurface 326, that extends into proximal channel 314 and presses onsheath body 322 so as to indent the sheath body and decrease the exposedsurface area of the drug core near the proximal end of the body. In someembodiments, optional annular rim 315 may press on the sheath body toretain the drug core in the channel without indentation of the sheathbody.

Retention structures 330 may comprise hydrogel rod 332, hydrogel coating336, protrusions 312 and protrusion 316. Hydrogel rod 332 can beinserted through the punctum into a canalicular lumen in a narrowprofile configuration. After insertion into the lumen hydrogel rod 332and hydrogel coating 336 can hydrate and expand to a wide profileconfiguration. Protrusions 312 and protrusion 316 can retain and/orstabilize implant 300 in the lumen, for example while the hydrogelcoating and rod expand.

FIG. 3C shows insertion of punctal plug 300 as in FIG. 3A into an uppercanaliculus of an eye. Punctal plug 300 can be oriented with hydrogelrod 332 aligned for placement in the upper canaliculus. Punctal plug 300can be advanced into vertical portion 10V of the canaliculus such thatthe exposed surface of the drug core and proximal end of the implant aresubstantially aligned with the exterior of the punctal opening.

FIG. 3D shows a punctal plug as in FIG. 3A in an expanded profileconfiguration following implantation in the canaliculus of the eye.Hydrogel rod 332 and hydrogel coating 336 are shown in an expandedprofile configuration.

FIG. 4 shows a drug core insert 400 suitable for use with an implant,according to embodiments of the present invention. Drug core insertcomprises a first proximal end 402 and a distal end 404. Drug coreinsert 400 comprises a sheath body 410, for example a polyimide tube.Sheath body 410 can comprise a material that is substantiallyimpermeable to the therapeutic agent such that flow of the therapeuticagent can be inhibited by the sheath body. Examples of materials thatcan be substantially impermeable to the therapeutic agent includepolyimide, polymethylmethacrylate (PMMA) and polyethylene terephthalate(PET). Sheath body 410 comprises a first proximal end 412 and a seconddistal end 414. Drug core insert 400 comprises a drug core 420comprising inclusions 424 encapsulated in a matrix material 426. Anexposed surface 422 comprising an area on the proximal end of the drugcore is capable of sustained release of the therapeutic agent attherapeutic levels, for example quantities. In many embodiments, thetherapeutic agent is at least partially soluble in the matrix material426 such that the therapeutic agent from the inclusions can penetratethe matrix material, for example via diffusion, and be released frommatrix material into a tissue surface and/or bodily fluid in contactwith exposed surface 422. A material 430 comprises distal end 404 of thedrug core insert. In many embodiments, the polyimide tube comprises acut length of tube in which the both ends of the tube have been cut toexpose the drug core. Material 430 can be adhered on the distal end ofthe drug core inserted to inhibit flow of the therapeutic agent. In manyembodiments, material 430 comprises an adhesive material that issubstantially impermeable to the therapeutic agent, for example acrylic,cyanoacrylate, epoxy, urethane, hot melt adhesives and loctite™ with UVcuring.

Sheath body 410 is sized to fit within a channel of an implant. Thedistal end of drug core insert 404 can be inserted into the implant suchthat exposed surface 422 remains exposed when the drug core insert isinserted into the implant.

FIG. 4B shows an example of implant 450 suitable for use with a drugcore insert 400 as in FIG. 4A, according to embodiments of the presentinvention. Implant 450 comprises a proximal 452 and a distal end 454.Implant 450 comprises a retention structure 460 that includes anindentation to retain implant 450 in the punctum of the eye. Implant 450comprises a channel 456 that extends from within the implant to anopening formed proximal end 452. Channel 456 can be sized to receivedrug core insert 400. Drug core insert 400 can be inserted into channel456 such that distal end 404 of drug core insert 400 is embedded withinimplant 450 while proximal end 402 comprising surface 422 is exposed.When implant 450 is placed in the punctum, surface 422 is exposed to thetear fluid of the eye such that the therapeutic agent can be deliveredto the eye. In many embodiments, the punctual plug has a length of about2 mm and a width of about 1 mm.

Many implants can be used with drug core insert 400. Some embodimentscan employ a commercially available implant, for example the Soft Plugsilicone punctum plug commercially Oasis Medical of Glendora California,the Tear Pool Punctal Plug commercially available form Medtronic, the“Parasol Punctal Occluder System” available from Odyssey of Memphis,Tenn., and/or the Eagle Vision Plug available from Eagle Vision ofMemphis, Tenn. In some embodiments, the punctual plug may comprise acustom punctual plug, for example sized custom plugs that are selectedin response to patient measurements. In some embodiments, the implantused with the drug core insert may comprise implants as described inU.S. application Ser. Nos. 11/695,537, filed on Apr. 2, 2007, entitled“DRUG DELIVERY METHODS, STRUCTURES, AND COMPOSITIONS FOR NASOLACRIMALSYSTEM”, published as U.S. patent Application Publication No.2007/0269487 on Nov. 22, 2007; 11/695,545, filed on Apr. 2,2007,entitled “NASOLACRIMAL DRAINAGE SYSTEM IMPLANTS FOR DRUG THERAPY”, whichissued as U.S. Pat. No. 7,998,497 on Aug. 16, 2011; 60/871,867, filed onDec. 26, 2006, entitled “DRUG DELIVERY IMPLANTS FOR INHIBITION OFOPTICAL DEFECTS”, the priority of which was claimed in PCT ApplicationNo. PCT/US2007/088701, which published as WO 2008/083118 on Jul. 10,2008; and Ser. No. 10/825,047, filed Apr. 15, 2004, entitled “DRUGDELIVERY VIA PUNCTAL PLUG,” published as U.S. Patent ApplicationPublication No. 2005/0232972 on Oct. 20, 2005; the full disclosures ofwhich are all incorporated herein by reference.

In some embodiments, such as shown in FIG. 36 and discussed in U.S.patent application Ser. No. 12/231,989, filed Sep. 8, 2008, entitled“LACRIMAL IMPLANTS AND RELATED METHODS”, and published as U.S. PatentApplication Publication No. 2009/0104248 on Apr. 23, 2009, the implantcan be insertable through a lacrimal punctum and into the associatedcanaliculus. The insertion of the implant through the lacrimal punctumand into the associated canaliculus can allow for one or more of:inhibition or blockage of tear flow therethrough (e.g., to treat dryeyes) or the sustained delivery of a drug or other therapeutic agent toan eye (e.g., to treat an infection, inflammation, glaucoma or otherocular disease or disorder), a nasal passage (e.g., to treat a sinus orallergy disorder) or an inner ear system (e.g., to treat dizziness or amigraine). The implant can comprise an implant body including first andsecond portions, and can extend from a proximal end of the first portionto a distal end of the second portion. In various examples, the proximalend can define a longitudinal proximal axis and the distal end candefine a longitudinal distal axis. The implant body can be configuredsuch that, when implanted within the lacrimal punctum and associatedcanaliculus, an at least 45 degree angled intersection exists betweenthe proximal axis and the distal axis for biasing at least a portion ofthe implant body against at least a portion of a lacrimal canaliculuslocated at or more distal to a canaliculus curvature. In some examples,the implant body can be configured such that the angled intersection isbetween about 45 degrees and about 135 degrees. In this example, theimplant body is configured such that the angled intersection is about 90degrees (i.e., the intersection is about perpendicular). In variousexamples, a distal end of the first portion can be integral with thesecond portion at or near a proximal end of the second portion.

In certain examples, the implant body can include angularly disposedcylindrical-like structures comprising one or both of a first cavitydisposed near the proximal end or a second cavity disposed near thedistal end. In this example, the first cavity extends inward from theproximal end of the first portion, and the second cavity extends inwardfrom the distal end of the second portion. A first drug-releasing orother agent-releasing drug core insert can be disposed in the firstcavity to provide a sustained drug or other therapeutic agent release toan eye, while a second drug core insert can be disposed in the secondcavity to provide a sustained drug or other therapeutic agent release toa nasal passage or inner ear system, for example. An implant body septumcan be positioned between the first cavity and the second cavity, andcan be used to inhibit or prevent communication of a material (e.g.,agent) between the first drug core insert and the second drug coreinsert. In some examples, the implant body is solid and does not includeone or more cavities or other voids.

FIG. 4C shows an annular drug core insert 470 suitable for use with animplant for systemic delivery of a therapeutic agent. Drug core insert470 comprises a sheath body 472 which is substantially impermeable tothe therapeutic agent so as to inhibit flow of the therapeutic agentthrough the sheath body. Drug core insert 470 comprises a solid drugcore 474. Drug core 474 comprises a matrix material with inclusions ofthe therapeutic agent dispersed therein, as described above. Drug core474 comprises an exposed surface 478. Drug core 474 comprises agenerally.annular shape with a channel 476 formed therein, such thatexposed surface 478 is inwardly directed and exposed to bodily fluids inthe channel, for example the tear liquid when implanted in the channel.Therapeutic quantities, or levels, of the therapeutic agent can bereleased from inner exposed surface 478 to the bodily fluid within thechannel

FIG. 4D shows an of implant 480 suitable for use with a drug core insertas in FIG. 4C. Implant 480 comprises a body 484, for example a moldedsilicone body, and retention structures 482. A channel 486 within body484 is sized to receive drug core insert 470. Implant 480 may comprise ahydrogel coating 488 on the outside. Hydrogel coating 488 may be locatednear retention structure 488. In some embodiments, hydrogel coating 488may be located away from the ends of implant 480, such that the hydrogeldoes not inhibit flow through channel 476 of the drug core insert whenimplanted in the patient. In some embodiments, the retention structuremay comprise an expandable coil or stent like structure with a proximalportion embedded in body 484 and an exposed distal portion that expandsto permit flow through the coil between the punctum and lacrimal sac,for example a shape memory capable of expansion to anchor the implant inthe canaliculus.

FIGS. 4E and 4F show a side cross-sectional view and an end view,respectively, of a drug core insert 490 comprising a first drug core 494and a second drug core 496. First drug core 494 comprises inclusions494I of a first therapeutic agent, and second drug core 496 comprisesinclusions 496I of a second therapeutic agent. Therapeutic quantities ofthe first therapeutic agent are released through an exposed surface 494Sof first drug core 494, and therapeutic quantities of a secondtherapeutic agent are released through an exposed surface 496S of seconddrug core 496.

Insert 490 comprises an outer sheath body 492 around drug core 496 andan inner sheath body 498 disposed between drug core 494 and drug core496, so as to inhibit release of one drug core to the other drug core.The sheath body 492 and sheath body 498 may comprise materialssubstantially impermeable to the therapeutic agent, so as to inhibitrelease of the therapeutic agent away from the exposed surfaces. In someembodiments, the sheath bodies may comprise thin walled tubes.

In some embodiments, the drug core insert can be used with an implantfor insertion in tissues in or near the eye, for example the sclera, theconjunctiva, the cul-de-sac of the eyelid, the trabecular meshwork, theciliary body, the cornea, the choroid, the suprachoroidal space, thesclera, the vitreous humor, aqueous humor and retina.

In some embodiments, the drug core insert can be manufactured with astructure to facilitate removal of the drug core insert, for example afilament as described in U.S. Application Ser. Nos. 60/970,696, filed onSep. 7, 2007, and 60/974,367 filed on Sep. 21, 2007 entitled “EXPANDABLENASOLACRIMAL DRAINAGE SYSTEM IMPLANTS”, the priorities of which areclaimed in U.S. patent application Ser. No. 12/231,989, filed Sep. 8,2008, entitled “LACRIMAL IMPLANTS AND RELATED METHODS”, and published asU.S. Patent Application Publication No. 2009/0104248 on Apr. 23, 2009;the full disclosures of which are all incorporated herein by reference.

FIGS. 5A to 5C schematically illustrate replacement of a drug core 510and a sheath body 520, according to an embodiment of the presentinvention. An implant 500 comprises drug core 510, sheath body 520 and aretention structure 530. Implant 500 can include an occlusive elementsupport by and movable with retention structure 530. Often retentionstructure 530 can assume a first small profile configuration prior toimplantation and a second large profile configuration while implanted.Retention structure 530 is shown in the large profile configuration andimplanted in the canalicular lumen. Sheath body 520 includes extension525A and extension 525B to attach the sheath body and drug core toretention structure 530 so that the sheath body and drug core areretained by retention structure 530. Drug core 510 and sheath body 520can be removed together by drawing drug core 510 proximally as shown byarrow 530. Retention structure 530 can remain implanted in thecanalicular tissue after drug core 510 and sheath body 520 have beenremoved as shown in FIG. 5B. A replacement core 560 and replacementsheath body 570 can be inserted together as shown in FIG. 5C. Suchreplacement can be desirable after drug core 510 has released effectiveamounts of therapeutic agent such that the supply of therapeutic agentin the drug core has diminished and the rate of therapeutic agentreleased is near the minimum effective level. Replacement sheath body570 includes extension 575A and extension 575B. Replacement drug core560 and replacement sheath body 570 can be advanced distally as shown byarrow 590 to insert replacement drug core 560 and replacement sheathbody 570 into retention structure 530. Retention structure 530 remainsat substantially the same location while replacement drug core 560 andreplacement sheath body 570 are inserted into resilient member 530.

FIGS. 5D and 5E show an implant comprising 800 a filament 810 thatextends from a drug core insert 808 for removal drug core insert 808from implant 800, according to embodiments of the present invention.Implant 800 comprises a body 805 and expandable retention structure 820,as described above. Body 810 comprises a proximal end 802 and a distalend 803. Implant 800 extends from proximal end 802 to a distal end 804of retention structure 820. Implant 800 comprises a channel to receivethe drug core insert, as described above. Filament 810 extends from aproximal end of the drug core insert to a distal end of the drug coreinsert. Filament 810 can be molded into the drug core insert. Filament840 may comprise many of the filaments described above, for example asuture, a thermoset polymer, a shape memory alloy, and the like.

FIG. 5F shows an implant 830 comprising a filament 840 that extendsalong a drug core insert 831 bonded to a distal end of the drug coreinsert for removal of the drug core insert from a body 832 of theimplant, according to embodiments of the present invention. Implant 830comprises a proximal end 833. Filament 840 may be bonded to the distalend of drug core insert 831 with an adhesive 842. Filament 840 can bebonded to the distal end of drug core insert 831 in many ways, forexample with cyanoacrylate, acrylic, epoxy, urethane and hot meltadhesives and the like.

Sheath Body

The sheath body comprises appropriate shapes and materials to controlmigration of the therapeutic agent from the drug core. The sheath bodyhouses the core and can fit snugly against the core. The sheath body ismade from a material that is substantially impermeable to thetherapeutic agent so that the rate of migration of the therapeutic agentmay be largely controlled by the exposed surface area of the drug corethat is not covered by the sheath body. In many embodiments, migrationof the therapeutic agent through the sheath body can be about one tenthof the migration of the therapeutic agent through the exposed surface ofthe drug core, or less, often being one hundredth or less. In otherwords, the migration of the therapeutic agent through the sheath body isat least about an order of magnitude less that the migration of thetherapeutic agent through the exposed surface of the drug core. Suitablesheath body materials include polyimide, polyethylene terephthalate”(hereinafter “PET”), polymethylmethacrylate (“PMMA”), stainless steel(for example, type 316 stainless steel, tubing size 25××), or titanium.The sheath body has a wall thickness from about 0.00025″ to about0.0015″. In some embodiments, the wall thickness can be defined as thedistance from the sheath surface adjacent the core to the opposingsheath surface away from the core. The total diameter of the sheath thatextends across the core ranges from about 0.2 mm to about 1.2 mm. Thecore may be formed by dip coating the core in the sheath material.Alternatively or in combination, the sheath body can comprise a tube andthe core introduced into the sheath, for example as a liquid or solidthat can be slid, injected and/or extruded into the sheath body tube.The sheath body can also be dip coated around the core, for example dipcoated around a pre-formed core.

The sheath body can be provided with additional features to facilitateclinical use of the implant. For example, the sheath may receive a drugcore that is exchangeable while the retention structure and sheath bodyremain implanted in the patient. The sheath body may be rigidly attachedto the retention structure as described above, and the core isexchangeable while the retention structure retains the sheath body. Inspecific embodiments, the sheath body can be provided with externalprotrusions that apply force to the sheath body when squeezed and ejectthe core from the sheath body. Another drug core can then be positionedin the sheath body. In many embodiments, the sheath body and/orretention structure may have a distinguishing feature, for example adistinguishing color, to show placement such that the placement of thesheath body and/or retention structure in the canaliculus or other bodytissue structure can be readily detected by the patient. The retentionelement and/or sheath body may comprise at least one mark to indicatethe depth of placement in the canaliculus such that the retentionelement and/or sheath body can be positioned to a desired depth in thecanaliculus based on the at least one mark.

Retention Structure

The retention structure comprises an appropriate material that is sizedand shaped so that the implant can be easily positioned in the desiredtissue location, for example the canaliculus. The retention structure ismechanically deployable and typically expands to a desired crosssectional shape, for example with the retention structure comprising asuper elastic shape memory alloy such as Nitinol™. Other materials inaddition to Nitinol™ can be used, for example resilient metals orpolymers, plastically deformable metals or polymers, shape memorypolymers, and the like, to provide the desired expansion. In someembodiments polymers and coated fibers available from Biogeneral, Inc.of San Diego, Calif. may be used. Many metals such as stainless steelsand non-shape memory alloys can be used and provide the desiredexpansion. This expansion capability permits the implant to fit inhollow tissue structures of varying sizes, for example canaliculaeranging from 0.3 min to 1.2 mm (i.e. one size fits all). Although asingle retention structure can be made to fit canaliculae from 0.3 to1.2 mm across, a plurality of alternatively selectable retentionstructures can be used to fit this range if desired, for example a firstretention structure for canaliculae from 0.3 to about 0.9 mm and asecond retention structure for canaliculae from about 0.9 to 1.2 mm. Theretention structure has a length appropriate to the anatomical structureto which the retention structure attaches, for example a length of about3 mm for a retention structure positioned near the punctum of thecanaliculus. For different anatomical structures, the length can beappropriate to provide adequate retention force, e.g. 1 mm to 15 mmlengths as appropriate.

Although the sheath body and drug core can be attached to one end of theretention structure as described above, in many embodiments the otherend of retention structure is not attached to drug core and sheath bodyso that the retention structure can slide over the sheath body and drugcore while the retention structure expands. This sliding capability onone end is desirable as the retention structure may shrink in length asthe retention structure expands in width to assume the desired crosssectional width. However, it should be noted that many embodiments mayemploy a sheath body that does not slide in relative to the core.

In many embodiments, the retention structure can be retrieved fromtissue. A protrusion, for example a hook, a loop, or a ring, can extendfrom the retention structure to facilitate removal of the retentionstructure.

Occlusive Element

The occlusive element comprises an appropriate material that is sizedand shaped so that the implant can at least partially inhibit, evenblock, the flow of fluid through the hollow tissue structure, forexample lacrimal fluid through the canaliculus. The occlusive materialshown is a thin walled membrane of a biocompatible material, for examplesilicone, that can expand and contract with the retention structure. Theocclusive element is formed as a separate thin tube of material that isslid over the end of the retention structure and anchored to one end ofthe retention structure as described above. Alternatively, the occlusiveelement can be formed by dip coating the retention structure in abiocompatible polymer, for example silicone polymer. The thickness ofthe occlusive element can be in a range from about 0.01 mm to about 0.15mm, and often from about 0.05 mm to 0.1 mm.

Therapeutic Agents

A “therapeutic agent” can comprise a drug and may be any of thefollowing or their equivalents, derivatives or analogs, including,anti-glaucoma medications, (e.g. adrenergic agonists, adrenergicantagonists (beta blockers), carbonic anhydrase inhibitors (CAIs,systemic and topical), parasympathomimetics, prostaglandins,prostaglandin analogs, and hypotensive lipids, and combinationsthereof), antimicrobial agent (e.g., antibiotic, antiviral,antiparacytic, antifungal, etc.), a corticosteroid or otheranti-inflammatory such as olopatadine (e.g., an NSAID), a decongestant(e.g., vasoconstrictor), an agent that prevents of modifies an allergicresponse (e.g., cyclosporine, an antihistamine, cytokine inhibitor,leucotriene inhibitor, IgE inhibitor, immunomodulator), a mast cellstabilizer, cycloplegic or the like. Examples of conditions that may betreated with the therapeutic agent(s) include but are not limited toglaucoma, pre and post surgical treatments, dry eye and allergies. Insome embodiments, the therapeutic agent may be a lubricant or asurfactant, for example a lubricant to treat dry eye.

Exemplary therapeutic agents include, but are not limited to, thrombininhibitors; antithrombogenic agents; thrombolytic agents; fibrinolyticagents; vasospasm inhibitors; vasodilators; antihypertensive agents;antimicrobial agents, such as antibiotics (such as tetracycline,chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin,tobramycin, gentamycin, erythromycin, penicillin, sulfonamides,sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole,nitrofurazone, sodium propionate), antifungals (such as amphotericin Band miconazole), and antivirals (such as idoxuridine trifluorothymidine,acyclovir, gancyclovir, interferon); inhibitors of surface glycoproteinreceptors; antiplatelet agents; antimitotics; microtubule inhibitors;anti-secretory agents; active inhibitors; remodeling inhibitors;antisense nucleotides; anti- metabolites; antiproliferatives (includingantiangiogenesis agents); anticancer chemotherapeutic agents;anti-inflaTnmatories (such as hydrocortisone, hydrocortisone acetate,dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone,prednisolone 21-phosphate, prednisolone acetate, fluoromethalone,betamethasone, triamcinolone, triamcinolone acetonide); non steroidalanti-inflammatories (NSAIDs) (such as salicylate, indomethacin,ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen,naxopren, piroxicam and nabumetone). Such anti inflammatory steroidscontemplated for use in the methodology of the present invention,include triamcinolone acetonide (generic name) and corticosteroids thatinclude, for example, triamcinolone, dexamethasone, fluocinolone,cortisone, prednisolone, flumetholone, and derivatives thereof);antiallergenics (such as sodium chromoglycate, antazoline,methapyriline, chlorpheniramine, cetrizine, pyrilamine,prophenpyridamine); anti proliferative agents (such as 1,3-cis retinoicacid, 5-fluorouracil, taxol, rapamycin, mitomycin C and cisplatin);decongestants (such as phenylephrine, naphazoline, tetrahydrazoline);miotics and anti- cholinesterase (such as pilocarpine, salicylate,carbachol, acetylcholine chloride, physostigmine, eserine, diisopropylfluorophosphate, phospholine iodine, demecarium bromide);antineoplastics (such as carmustine, cisplatin, fluorouracil3;immunological drugs (such as vaccines and immune stimulants); hormonalagents (such as estrogens, -estradiol, progestational, progesterone,insulin, calcitonin, parathyroid hormone, peptide and vasopressinhypothalamus releasing factor); immunosuppressive agents such ascyclosporine, growth hormone antagonists, growth factors (such asepidermal growth factor, fibroblast growth factor, platelet derivedgrowth factor, transforming growth factor beta, somatotrapin,fibronectin); inhibitors of angiogenesis (such as angiostatin,anecortave acetate, thrombospondin, anti-VEGF antibody); dopamineagonists; radiotherapeutic agents; peptides; proteins; enzymes;extracellular matrix; components; ACE inhibitors; free radicalscavengers; chelators; antioxidants; anti polymerases; photodynainictherapy agents; gene therapy agents; and other therapeutic agents suchas prostaglandins, antiprostaglandin, prostaglandin precursors,including antiglaucoma drugs including beta-blockers such as Timolol,betaxolol, levobunolol, atenolol, and prostaglandin analogues such asBimatoprost, travoprost, Latanoprost etc; carbonic anhydrase inhibitorssuch as acetazolamide, dorzolamide, brinzolamide, methazolamide,dichlorphenamide, diamox; and neuroprotectants such as lubezole,nimodipine and related compounds; and parasympathomimetrics such aspilocarpine, carbachol, physostigmine and the like.

For use in ophthalmic applications, some specific therapeutic agentsthat can be used include glaucoma medications (muscarinics, betablockers, alpha agonists, carbonic anhydrase inhibitors, prostaglandinsand their analogs), antiinflammatories (steroids, soft steroids,NSAIDs), anti infectives including antibiotics such as beta lactams,fluoro quinolones, etc.), antivirals, and antimicotics, dry eyemedications (CsA, delmulcents, sodium hyaluronate), or combinationsthereof.

The amount of drug associated with the drug-delivery device may varydepending on the particular agent, the desired therapeutic benefit andthe time during which the device is intended to deliver the therapy.Since the devices of the present invention present a variety of shapes,sizes and delivery mechanisms, the amount of drug associated with thedevice will depend on the particular disease or condition to be treated,and the dosage and duration that is desired to achieve the therapeuticeffect. Generally, the amount of drug is at least the amount of drugthat upon release from the device, is effective to achieve the desiredphysiological or pharmacological effects.

Embodiments of the drug delivery devices of the present invention can beadapted to provide delivery of drug at a daily rate that issubstantially below the therapeutically effective drop form of treatmentso as to provide a large therapeutic range with a wide safety margin.For example, many embodiments treat the eye with therapeutic levels forextended periods that are no more than 5 or 10 per cent of the dailydrop dosage. Consequently, during an initial period of about seven days,more typically of about one to three days, the implant can elute thetherapeutic agent at a rate that is substantially higher than thesustained release levels but still below the daily drop form dosage. Forexample, with an average sustained release level of 100 ng per day, andan initial release rate of 1000 to 1500 ng per day, the amount of druginitially released is less than the 2500 ng of drug that may be presentin a drop of drug delivered to the eye. This use of sustained releaselevels substantially below the amount of drug in a drop and/or dropsadministered daily allows the device to release a therapeuticallybeneficial amount of drug to achieve the desired therapeutic benefitwith a wide safety margin, while avoiding an inadequate or excessiveamount of drug at the intended site or region.

An extended period of time may mean a relatively short period of time,for example minutes or hours (such as with the use of an anesthetic),through days or weeks (such as the use of pre-surgical or post-surgicalantibiotics, steroids, or NSAIDs and the like), or longer (such as inthe case of glaucoma treatments), for example months or years (on arecurring basis of use of the device).

For example, drug such as Timolol maleate, a betal and beta2(non-selective) adrenergic receptor blocking agent can be used in thedevice for a release over an extended period of time such as 3 months.Three months is a relatively typical elapsed time between physicianvisits for a glaucoma patient undergoing topical drop therapy with aglaucoma drug, although the device could provide treatment for longer orshorter durations. In the three month example, a 0.25% concentration ofTimolol translates to from 2.5 to 5 mg/1000 μL, typically being 2.5mg/1000 μL. A drop of Timolol for topical application is usually in therange of 40-60 μL, typically being 50 μL. Thus, there may be 0.08-0.15mg, typically being 0.125 mg of Timolol in a drop. There may beapproximately 8% (e.g. 6-10%) of the drop left in the eye after 5minutes, so about 10 μg of the drug is available at that time. Timololmay have a bioavailability of 30-50%, which means that from 1.5 to 7.5μg, for example 4 μg of the drug is available to the eye. Timolol isgenerally applied twice a day, so 8 (or 3-15)μg is available to the eyeeach day. Therefore, a delivery device might contain from 270 to 1350 g,for example 720 μg, of the drug for a 90 day, or 3 month, extendedrelease. The drug would be contained within the device and eluted basedon the design of the device, including the polymers used and the surfacearea available for drug elution. The drug can be similarly contained onthe device and eluted for olopatadine hydrochloride (Patanol®) and otherdrugs in a manner similar to Timolol.

Commercially available solutions of Timolol maleate are available in0.25% and 0.5% preparations, and the initial dosage can be 1 drop twiceper day of 0.25% solution. A 0.25% concentration of Timolol isequivalent to 2.5 mg per 1000 μl. A sustained release quantity ofTimolol released each day from the drug core can be from about 3 to 15μg each day. Although the sustained release quantity delivered each dayfrom the device may vary, a sustained release delivery of about 8 μg perday corresponds to about 3.2% of the 0.250 mg of Timolol applied withtwo drops of a 0.25% solution.

For example, in the case of Latanoprost (Xalatan), a prostaglandin F2αanalogue, this glaucoma medication has concentrations that are about1/50th that of Timolol. Therefore, the amount of drug on the implantabledevice, depending on the bioavailability, would be significantlyless—approximately 5-135 μg and typically 10-50 μg—for Latanoprost andother prostaglandin analogues. This also translates to a device that caneither be smaller than one required for a beta blocker delivery or canhouse more drug for a longer release period.

A drop of Xalatan contains about 2.5 μg of Latanoprost, assuming a 50 μLdrop volume. Therefore, assuming that about 8% of 2.5 μg is present 5minutes after instillation, only about 200 ng of drug remains on theeye. Based on the Latanoprost clinical trials, this amount is effectivein lowering IOP for at least 24 hours. Pfizer/Pharmacia conductedseveral dose-response studies in support of the NDA for Xalatan. Thedoses ranged from 12.5 μg/mL to 115 μg/mL of Latanoprost. The currentdose of Latanoprost, 50 pg/mL, given once per day, was shown to beoptimal. However, even the lowest doses of 12.5 μg/mL QD or 15 μg/mL BIDconsistently gave about 60-75% of the IOP reduction of the 50 μg/mL QDdose. Based on the assumptions above, a 12.5 μg/mL concentrationprovides 0.625 μg of Latanoprost in a 50 μL drop, which results in onlyabout 50 ng (8%) of drug remaining in the eye after 5 minutes.

In many embodiments, the concentrations of Latanoprost are about1/100th, or 1 per cent, that of Timolol, and in specific embodiments theconcentrations of Latanoprost may be about 1/50th, or 2 percent, that ofTimolol. For example, commercially available solution preparations ofLatanoprost are available at concentrations 0.005%, often delivered withone drop per day. In many embodiments, the therapeutically effectiveconcentration of drug released from the device per day can be about1/100th of Timolol, about 30 to 150 ng per day, for example about 80 ng,assuming tear washout and bioavailability similar to Timolol. Forexample, the amount of drug on the implantable device, can besignificantly less- approximately 1% to 2% of Timolol, for example 2.7to 13.5 μg, and can also be about 3 to 20 μg, for Latanoprost and otherprostaglandin analogues. Although the sustained release amount ofLatanoprost released each day can vary, a sustained release of 80 ng perday corresponds to about 3.2% of the 2.5 μg of Latanoprost applied witha single drop of a 0.005% solution.

For example, in the case of Bimatoprost (Lumigan), a syntheticprostamide prostaglandin analogue, this glaucoma medication may haveconcentrations that are 1/20th or less than that of Timolol. Therefore,the amount of drug loaded on the extended release device for a 3 to 6month extended release, depending on the bioavailability, can besignificantly less, approximately 5-30 μg and typically 10-20 μg—forBimatoprost and analogues and derivatives thereof. In many embodiments,the implant can house more drug for a longer sustained release period,for example 20-40 μg for a sustained release period of 6 to 12 monthswith Bimatoprost and its derivatives. This decrease in drugconcentration can also translate to a device that can be smaller thanone required for a beta blocker delivery.

Commercially available solution concentrations of Bimatoprost are 0.03%by weight, often delivered once per day. Although the sustained releaseamount of Bimatoprost released each day can vary, a sustained release of300 ng per day corresponds to about 2% of the 15 μg of Bimatoprostapplied with a single drop of a 0.03% solution. Work in relation withthe present invention suggests that even lower sustained release dosesof Bimatoprost can provide at least some reduction in intraocularpressure, for example 20 to 200 ng of Bimatoprost and daily sustainedrelease dosages of 0.2 to 2% of the daily drop dosage.

For example, in the case of Travoprost (Travatan), a prostaglandin F2αanalogue, this glaucoma medication may have concentrations that are 2%or less than that of Timolol. For example, commercially availablesolution concentrations are 0.004%, often delivered once per day. Inmany embodiments, the therapeutically effective concentration of drugreleased from the device per day can be about 65 ng, assuming tearwashout and bioavailability similar to Timolol. Therefore, the amount ofdrug on the implantable device, depending on the bioavailability, wouldbe significantly less. This also translates to a device that can eitherbe smaller than one required for a beta blocker delivery or can housemore drug for a longer release period. For example, the amount of drugon the implantable device, can be significantly less- approximately1/100 of Timolol, for example 2.7 to 13.5 μg, and typically about 3 to20 μg, for Travoprost, Latanoprost and other prostaglandin F2αanalogues. Although the sustained release amount of Latanoprost releasedeach day can vary, a sustained release of 65 ng per day corresponds toabout 3.2% of the 2.0 μg of Travoprost applied with a single drop of a0.004% solution.

In some embodiments, the therapeutic agent may comprise acorticosteriod, for example fluocinolone acetonide, to treat a targetocular tissue. In specific embodiments, fluocinolone acetonide can bereleased from the canaliculus and delivered to the retina as a treatmentfor diabetic macular edema (DME).

It is also within the scope of this invention to modify or adapt thedevices to deliver a high release rate, a low release rate, a bolusrelease, a burst release, or combinations thereof. A bolus of the drugmay be released by the formation of an erodable polymer cap that isimmediately dissolved in the tear or tear film As the polymer cap comesin contact with the tear or tear film, the solubility properties of thepolymer enable the cap to erode and the drug is released all at once. Aburst release of a drug can be performed using a polymer that alsoerodes in the tear or tear film based on the polymer solubility. In thisexample, the drug and polymer may be stratified along the length of thedevice so that as the outer polymer layer dissolves, the drug isimmediately released. A high or low release rate of the drug could beaccomplished by changing the solubility of the erodable polymer layer sothat the drug layer released quickly or slowly. Other methods to releasethe drug could be achieved through porous membranes, soluble gels (suchas those in typical ophthalmic solutions), microparticle encapsulationsof the drug, or nanoparticle encapsulation, depending on the size of thedrug molecule.

Drug Core

The drug core comprises the therapeutic agent and matrix materials toprovide sustained release of the therapeutic agent. The matrix materialcan include a polymer, such as silicone or polyurethane. The therapeuticagent migrates from the drug core to the target tissue, for example theciliary body of the eye. The therapeutic agent may optionally be onlyslightly soluble in the matrix so that a small amount of therapeuticagent is dissolved in the matrix and available for release from thesurface of drug core 110, additional agent being present in the form ofinclusions, which can be in a solid or a liquid physical state withinthe matrix. As the therapeutic agent diffuses from the exposed surfaceof the core to the tear or tear film, the rate of migration from thecore to the tear or tear film can be related to the concentration oftherapeutic agent dissolved in the matrix. In addition or incombination, the rate of migration of therapeutic agent from the core tothe tear or tear film can be related to properties of the matrix inwhich the therapeutic agent dissolves. In specific embodiments, the rateof migration from the drug core to the tear or tear film can be based ona silicone formulation. In some embodiments, the concentration oftherapeutic agent dissolved in the drug core may be controlled toprovide the desired rate of release of the therapeutic agent. Thetherapeutic agent included in the core can include liquid, solid, solidgel, solid crystalline, solid amorphous, solid particulate, and/ordissolved forms of the therapeutic agent. In an embodiment, the drugcore comprises a silicone matrix containing the therapeutic agent. Thetherapeutic agent may comprise liquid or solid inclusions, for exampleliquid latanoprost droplets or solid bimatoprost particles,respectively, dispersed in the silicone matrix. The average diameter,and the distribution of diameters throughout the population of dropletsor particles, can be used to control the elution rate of the agent fromthe drug core into, for example, tear liquid in the eye.

In another embodiment, the therapeutic agent can be soluble atrelatively high levels in the matrix, such that inclusions are notformed when the agent is present at therapeutically usefulconcentrations. For example, cyclosporine can be dissolved in apolyurethane matrix at high concentrations, and the cyclosporine isdispersed throughout the polyurethane matrix at molecular levels, i.e.,a “solid solution” of the cyclosporine in the polyurethane matrix can beachieved.

When the inclusion is solid, various comminuted forms of the solidmaterial can be used to achieve a particular average particle diameterand size distribution of dimeters. Such solid powders can be obtained byany suitable method known in the art. See, for example, machinesmanufactured for the pharmaceutical industry by Glatt GmbH, athttp://www.glatt.com/e/00_home/00.htm. In the milling process a range ofsizes can be generated. Fluidized beds and coaters can be used toincrease particle size to a desired dimension. Particle size willinfluence surface area and may affect dissolution. Inclusion size andassociated size distribution can be used to control an elution rate ofthe agent from the drug core, both in the situation where the inclusionsare solid, such as bimatoprost, and where the inclusions are liquid,such as latanoprost oil.

The drug core can comprise one or more biocompatible materials capableof providing a sustained release of the therapeutic agent. Although thedrug core is described above with respect to an embodiment comprising amatrix with a substantially non-biodegradable silicone matrix withinclusions of the drug located therein that dissolve, the drug core caninclude structures that provide sustained release of the therapeuticagent, for example a biodegradable matrix, a porous drug core, liquiddrug cores and solid drug cores. A matrix that contains the therapeuticagent can be formed from either biodegradable or non-biodegradablepolymers. A non-biodegradable drug core can include silicone, acrylates,polyethylenes, polyurethane, polyurethane, hydrogel, polyester (e.g.,DACRON® from E. I. Du Pont de Nemours and Company, Wilmington, Del.),polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE),polyether ether ketone (PEEK), nylon, extruded collagen, polymer foam,silicone rubber, polyethylene terephthalate, ultra high molecular weightpolyethylene, polycarbonate urethane, polyurethane, polyimides,stainless steel, nickel-titanium alloy (e.g., Nitinol), titanium,stainless steel, cobalt-chrome alloy (e.g., ELGILOY® m Elgin SpecialtyMetals, Elgin, Ill; CONICHROME® from Carpenter Metals Corp., Wyomissing,Pa.). A biodegradable drug core can comprise one or more biodegradablepolymers, such as protein, hydrogel, polyglycolic acid (PGA), polylacticacid (PLA), poly(L-lactic acid) (PLLA), poly(L-glycolic acid) (PLGA),polyglycolide, poly-L-lactide, poly-D-lactide, poly(amino acids),polydioxanone, polycaprolactone, polygluconate, polylacticacid-polyethylene oxide copolymers, modified cellulose, collagen,polyorthoesters, polyhydroxybutyrate, polyanhydride, polyphosphoester,poly(alpha-hydroxy acid) and combinations thereof. In some embodimentsthe drug core can comprise at least one of hydrogel polymer.

Release of Therapeutic Agent at Effective Levels

The rate of release of the therapeutic agent can be related to theconcentration of therapeutic agent in the drug core. In manyembodiments, the drug core comprises non-therapeutic agents that areselected to provide a desired solubility of the therapeutic agent in thedrug core. The non-therapeutic agent of the drug core can comprisepolymers as described herein and additives. A polymer of the core can beselected to provide the desired solubility and/or dispersability of thetherapeutic agent in the matrix. For example, the core can comprisehydrogel that may promote solubility or dispersability of hydrophilictreatment agent. In some embodiments, functional groups can be added tothe polymer to provide the desired solubility or dispersity of thetherapeutic agent in the matrix. For example, functional groups can beattached to silicone polymer.

In some embodiments, release rate modifying additives may be used tocontrol the release kinetics of therapeutic agent. For example, theadditives may be used to control the concentration of therapeutic agentby increasing or decreasing solubility of the therapeutic agent in thedrug core so as to control the release kinetics of the therapeuticagent. The solubility may be controlled by providing appropriatemolecules and/or substances that increase and/or decrease the solubilityof the therapeutic agent to the matrix. The solubility of thetherapeutic agent may be related to the hydrophobic and/or hydrophilicproperties of the matrix and therapeutic agent. For example,surfactants, tinuvin, salts and water can be added to the matrix and mayincrease the solubility of hydrophilic therapeutic agent in the matrix.Salts can be water soluble, such as sodium chloride, or water-insoluble,such as titanium dioxide. In addition, oils and hydrophobic moleculesand can be added to the matrix and may increase the solubility ofhydrophobic treatment agent in the matrix. Alternatively, variousoligomers and polymers, for example polysaccharides such as alginates,or proteins such as albumin, can be added. Solvents such as glycerol canalso be used to modify the rate of release of the agent from the matrixinto the tear liquid.

Instead of or in addition to controlling the rate of migration based onthe concentration of therapeutic agent dissolved in the matrix, thesurface area of the drug core can also be controlled to attain thedesired rate of drug migration from the core to the target site. Forexample, a larger exposed surface area of the core will increase therate of migration of the treatment agent from the drug core to thetarget site, and a smaller exposed surface area of the drug core willdecrease the rate of migration of the therapeutic agent from the drugcore to the target site. The exposed surface area of the drug core canbe increased in any number of ways, for example by any of castellationof the exposed surface, a surface having exposed channels connected withthe tear or tear film, indentation of the exposed surface, protrusion ofthe exposed surface. The exposed surface can be increased by theaddition of salts that dissolve and leave cavities once the saltdissolves. Hydrogels may also be used, and can swell in size to providea larger exposed surface area.

In addition, drug impregnated porous materials, such as meshes, may beused such as those disclosed in U.S. Patent Application Publication No.2002/0055701 or layering of biostable polymers as described in U.S.Patent Application Publication No. 2005/0129731. Certain polymerprocesses may be used to incorporate drug into the devices of thepresent invention such as, so-called “self-delivering drugs” orPolymerDrugs (Polymerix Corporation, Piscataway, NJ) are designed todegrade only into therapeutically useful compounds and physiologicallyinert linker molecules, further detailed in US Patent Publication No.2005/0048121 (East), hereby incorporated by reference in its entirety.Such delivery polymers may be employed in the devices of the presentinvention to provide a release rate that is equal to the rate of polymererosion and degradation and is constant throughout the course oftherapy. Such delivery polymers may be used as device coatings or in theform of microspheres for a drug depot injectable (such as a reservoir ofthe present invention). A further polymer delivery technology may alsobe adapted to the devices of the present invention such as thatdescribed in U.S. Patent Application Publication No. 2004/0170685(Carpenter), and technologies available from Medivas (San Diego,Calif.).

In specific embodiments, the drug core matrix comprises a solidmaterial, for example silicone, that encapsulates inclusions of thedrug. The drug comprises molecules which are very insoluble in water andslightly soluble in the encapsulating drug core matrix. The inclusionsencapsulated by the drug core can be micro-particles having dimensionsfrom about 1 μm to about 100 μm across. The drug inclusions can comprisecrystals, for example bimatoprost crystals, and/or droplets of oil, forexample with latanoprost oil. The drug inclusions can dissolve into thesolid drug core matrix and substantially saturate the drug core matrixwith the drug, for example dissolution of latanoprost oil into the soliddrug core matrix. The drug dissolved in the drug core matrix istransported, often by diffusion, from the exposed surface of the drugcore into the tear film As the drug core is substantially saturated withthe drug, in many embodiments the rate limiting step of drug delivery istransport of the drug from the surface of the drug core matrix exposedto the tear film. As the drug core matrix is substantially saturatedwith the drug, gradients in drug concentration within the matrix areminimal and do not contribute significantly to the rate of drugdelivery. As surface area of the drug core exposed to the tear film isnearly constant, the rate of drug transport from the drug core into thetear film can be substantially constant. Work in relation with thepresent invention suggests that the solubility of the therapeutic agentin water and molecular weight of the drug can effect transport of thedrug from the solid matrix to the tear. In many embodiments, thetherapeutic agent is nearly insoluble in water and has a solubility inwater of about 0.03% to 0.002% by weight and a molecular weight fromabout 400 grams/mol. to about 1200 grams/mol.

In many embodiments the therapeutic agent has a very low solubility inwater, for example from about 0.03% by weight to about 0.002% by weight,a molecular weight from about 400 grams per mole (g/mol.) to about 1200g/mol and is readily soluble in an organic solvent. Cyclosporin A (CsA)is a solid with an aqueous solubility of 27.67 μg/mL at 25° C., or about0.0027% by weight, and a molecular weight (M.W.) of 1202.6 g/mol.Latanoprost (Xalatan) is a prostaglandin F2α analogue, a liquid oil atroom temperature, and has an aqueous solubility of 50 μg/mL in water at25° C., or about 0.005% by weight and a M.W. of 432.6 g/mol.

Bimatoprost (Lumigan) is a synthetic prostamide analogue, a solid atroom temperature solubility in water of 300 μg/mL in water at 25° C., or0.03% by weight, and has a M.W. of 415.6 g/mol.

Work in relation with the present invention indicates that naturallyoccurring surfactants in the tear film, for example surfactant D andphospholipids, may effect transport of the drug dissolved in the solidmatrix from the core to the tear film The drug core can be adapted inresponse to the surfactant in the tear film to provide sustaineddelivery of the drug into the tear film at therapeutic levels. Forexample, empirical data can be generated from a patient population, forexample 10 patients whose tears are collected and analyzed forsurfactant content. Elution profiles in the collected tears for a drugthat is sparingly soluble in water, for example cyclosporine, can alsobe measured and compared with elution profiles in buffer and surfactantsuch that an in vitro model of tear surfactant is developed. An in vitrosolution with surfactant based on this empirical data can be used toadjust the drug core in response to the surfactant of the tear film.

The drug cores may also be modified to utilize carrier vehicles such asnanoparticles or microparticles depending on the size of the molecule tobe delivered such as latent-reactive nanofiber compositions forcomposites and nanotextured surfaces (Innovative Surface Technologies,LLC, St. Paul, Minn.), nanostructured porous silicon, known asBioSilicon®, including micron sized particles, membranes, woven fiversor micromachined implant devices (pSividia, Limited, UK) and proteinnanocage systems that target selective cells to deliver a drug(Chimeracore).

In many embodiments, the drug insert comprises of a thin-walledpolyimide tube sheath with a drug core comprising latanoprost dispersedin Nusil 6385 (MAF 970), a medical grade solid silicone that serves asthe matrix for drug delivery. The distal end of the drug insert issealed with a cured film of solid Loctite 4305 medical grade adhesive.The drug insert may be placed within the bore of the punctum plug, theLoctite 4305 adhesive does not come into contact with either tissue orthe tear film. The inner diameter of the drug insert can be 0.32 mm; andthe length can be 0.95 mm. Three Latanoprost concentrations in thefinished drug product can be tested clinically: Drug cores can comprise3.5, 7 or 14 μg latanoprost, with per cent by weight concentrations of5, 10 and 20% respectively. Assuming an overall elution rate ofapproximately 100 ng/day, the drug core comprising 14 μg of latanoprostis adapted to deliver drug for approximately at least 100 days, forexample 120 days. The overall weight of the drug core, includinglatanoprost, can be ˜70 μg. The weight of the drug insert including thepolyimide sleeve can be approximately 100 μg.

In many embodiments, the drug core may elute with an initial elevatedlevel of therapeutic agent followed by substantially constant elution ofthe therapeutic agent. In many instances, an amount of therapeutic agentreleased daily from the core may be below the levels found in drops andstill provide a benefit to the patient. An elevated level of elutedtherapeutic agent can result in a residual amount of therapeutic agentand/or residual effect of the therapeutic agent to provide relief to thepatient. In embodiments where therapeutic level is about 80 ng per day,the device may deliver about 100 ng per day for an initial deliveryperiod. The extra 20 ng delivered per day can have a beneficialimmediate effect. As the amount of drug delivered can be preciselycontrolled, an initial elevated dose may not result in complicationsand/or adverse events to the patient.

Further, an implant may be used that includes the ability to release twoor more drugs in combination, such as the structure disclosed in U.S.Pat. No. 4,281,654 (Shell). For example, in the case of glaucomatreatment, it may be desirable to treat a patient with multipleprostaglandins or a prostaglandin and a cholinergic agent or anadrenergic antagonist (beta blocker), such as Alphagan®, orprostaglandin and a carbonic anhydrase inhibitor.

In various embodiments, the implant may have at least one surface andrelease a therapeutic quantity of two therapeutic agents into tear ortear film fluid of the eye throughout a time period of at least one weekwhen the implant is implanted with the at least one surface exposed tothe tear or tear film fluid. For example, the implant can be adapted torelease the therapeutic agents in therapeutic amounts over a period oftime from about one to twelve months. The release rate of each of thetherapeutic agents may be the same or each of the therapeutic agents mayhave different release rates.

In some embodiments, the implant comprise a single drug core with twotherapeutic agents mixed within a matrix. In other embodiments, theimplant comprise two drug cores, each with a single therapeutic agent.

In specific embodiments, at least a portion of the implant may bebioerodable, and the therapeutic agents can be released while the aportion of the implant erodes.

In some embodiments, the second therapeutic agent may comprise acounteractive agent to avoid a side effect of the first therapeuticagent. In one example, the second therapeutic agent may comprise atleast one of an anti-glaucoma drug or a miotic drug. The anti-glaucomadrug may comprise at least one of a sympathomimetic, aparasympathomimetic, a beta blocking agent, a carbonic anhydraseinhibitor, or prostaglandin analogue. In another example, the firsttherapeutic agent may be steroids and the second therapeutic agent maybe antibiotics, where the steroids compromise the immune response, butthe antibiotics provides coverage for infection. In another example, thefirst therapeutic agent may be pilocarpine and the second therapeuticagent may be non-steroidal anti-inflammatory drug (NSAID). An analgesicmay be a good compliment for the treatment.

In some embodiments the therapeutic agents can be released with aprofile that corresponds to a kinetic order of therapeutic agentsrelease and the order can be within a range from about zero to aboutone. In specific embodiments, the range is from about zero to about onehalf, for example from about zero to about one quarter. The therapeuticagents may be released with a profile that corresponds to a kineticorder of therapeutic agents release and the order is within a range fromabout zero to about one half for at least about a month after thestructure is inserted, for example the order can be within the range atleast about 3 months after the structure is inserted.

Referring now to FIG. 17, an implant, for example a punctal plug 1700,is shown which comprises a silicone body 1710, a drug core 1720 and aretention structures 1730, according to embodiments of the presentinvention. Body 1710 comprises a proximal channel 1714 sized to receivedrug core insert 1720. A filament 1734 can be embedded in body 1710 andwrapped around hydrogel rod 1732 to affix hydrogel rod 1732 to body1710. The drug core insert and manufacture of the drug core insert aredescribed in U.S. application Ser. Nos. 11/695,537 and 11/695,545, thefull disclosures of which are incorporated herein by reference. Althougha drug core insert is shown, some embodiments may comprises a drugreservoir, a semi-permeable membrane, a drug coating or the like, asdescribed in U.S. Pat. No. 6,196,993 (Cohan) and U.S. application Ser.Nos. 10/899,416 (Prescott); 10/899,417 (Prescott); 10/762,421(Ashton);10/762,439 (Ashton); 11/571,147 (Lazar) and 10/825,047 (Odrich), thefull disclosures of which are herein incorporated by reference for allpurposes. In some embodiments, the implant comprises a punctal plugwithout drug carried on the implant, for example an implant similar topunctal plug 1700 without channel 1714 and drug core insert 1720.

Retention structures 1730 may comprise hydrogel rod, hydrogel coating,and protrusions. Hydrogel rod 1732 can be inserted through the punctuminto a canalicular lumen in a narrow profile configuration. Afterinsertion into the lumen the hydrogel rod, hydrogel coating, or both,can hydrate expand to a wide profile configuration.

FIG. 18A shows a cross sectional view of a sustained release implant1800 having two therapeutic agents to treat an eye, according toembodiments of the present invention. Implant 1800 has a proximal end1812 in which the therapeutic agents are released and a distal end 1814.Implant 1800 includes two concentric drug cores 1810, 1815. First drugcore 1810 is a cylindrical shaped structure with a central opening thatincludes a first therapeutic agent, and second drug core 1815 is acylindrical shaped structure that includes a second therapeutic agent.Second drug core 1815 is configured to fit within the central opening offirst drug core 1810, as shown in the figures. First drug core 1810comprises a first matrix 1870 that contains first inclusions 1860 of thefirst therapeutic agent, and second drug core 1815 comprises a secondmatrix 1875 that contains second inclusions 1865 of the secondtherapeutic agent. First and second inclusions 1860, 1865 will oftencomprise a concentrated form of the first and second therapeutic agents,for example a liquid or solid form of the therapeutic agents, and thetherapeutic agents may over time dissolve into first matrix 1870 offirst drug core 1810 and second matrix 1875 of second drug core 1815.First and second matrixes 1870, 1875 can comprise a silicone matrix orthe like, and the mixture of therapeutic agents within matrixes can benon-homogeneous. In many embodiments, the non-homogenous mixturecomprises a silicone matrix portion that is saturated with thetherapeutic agents and an inclusions portion comprising inclusions ofthe therapeutic agents, such that the non-homogenous mixture comprises amultiphase non-homogenous mixture. The first matrix may differ from thesecond matrix, including, for example, an exposed surface area, asurfactant, a cross-linking, an additive, and/or matrix materialsincluding formulation and/or solubility. In some embodiments, first andsecond inclusions 1860, 1865 comprise droplets of an oil of thetherapeutic agent, for example Latanoprost oil. In some embodiments,first and second inclusions 1860, 1865 may comprise particles of thetherapeutic agents, for example solid bimatoprost particles. In manyembodiments, first matrix 1870 contains first inclusions 1860 and secondmatrix 1875 contains second inclusions 1865. First and second inclusions1860, 1865 may comprise microparticles having dimensions from about 0.1μm to about 100 μm, or 200 μm. The contained inclusions at leastpartially dissolve into the surrounding solid matrix, for examplesilicone, that contains the micro particles such that first and secondmatrixes 1870, 1875 are substantially saturated with the therapeuticagent while the therapeutic agent is released from the core.

First and second drug cores 1810, 1815 are surrounded by a sheath body1820, except at an exposed surface where the therapeutic agents arereleased, in this case at the proximal end 1812. Sheath body 1820 issubstantially impermeable to the therapeutic agents, so that thetherapeutic agents are released from the exposed surface on the open endof first and second drug cores 1810, 1815 that are not covered withsheath body 1820. In some embodiments, the implant may be incorporatedinto a different structure, such as a punctal plug.

FIG. 18B shows a side cross sectional view of the sustained releaseimplant of FIG. 18A. First drug core 1810 with a first therapeutic agentis a cylindrical shaped structure and shown with a circularcross-section with an open center. Second drug core 1815 with a secondtherapeutic agent is a cylindrical shaped structure and shown with acircular cross-section and is configured to fit within first drug core1810, as shown in the figures. Sheath body 1820 comprises an annularportion disposed on first drug core 310.

FIG. 19A shows a cross sectional view of a sustained release implant1900 having therapeutic agents to treat an eye, according to embodimentsof the present invention. Implant 1900 has a proximal end 1912 in whichthe therapeutic agents are released and a distal end 1914. Implant 1900includes first and second drug cores 1910, 1915 that are positioned in aside by side configuration. First drug core 1910 is a cylindrical shapedstructure that includes the first therapeutic agent and second drug core1915 is a cylindrical shaped structure that includes the secondtherapeutic agent. First and second drug cores 1910 and 1915 are placedadjacent to each other and may have the same length, or differentlengths, such as shown in the figure. First drug core 1910 comprises afirst matrix 1970 that contains first inclusions 1960 of the firsttherapeutic agent and second drug core 415 comprises a second matrix1975 that contains second inclusions 1965 of the second therapeuticagent. First and second inclusions 1960, 1965 will often comprise aconcentrated form of the first and second therapeutic agents, forexample a liquid or solid form of the therapeutic agents, and thetherapeutic agents may over time dissolve into first matrix 1970 offirst drug core 1910 and second matrix 1975 of second drug core 1915.First and second matrixes 1970, 1975 can comprise a silicone matrix orthe like, and the mixture of therapeutic agents within matrixes can benon-homogeneous. In many embodiments, the non-homogenous mixturecomprises a silicone matrix portion that is saturated with thetherapeutic agents and an inclusions portion comprising inclusions ofthe therapeutic agents, such that the non-homogenous mixture comprises amultiphase non-homogenous mixture. The first matrix may differ from thesecond matrix, including, for example, an exposed surface area, asurfactant, a cross-linking, an additive, and/or matrix materialsincluding formulation and/or solubility. In some embodiments, first andsecond inclusions 1960, 1965 comprise droplets of an oil of thetherapeutic agent, for example Latanoprost oil. In some embodiments,inclusions may comprise particles of the therapeutic agent, for examplesolid bimatoprost particles. First and second inclusions 1960, 1965 maycomprise microparticles having dimensions from about 0.1 μm to about 100μm, or 200 μm. The contained inclusions at least partially dissolve intothe surrounding solid matrix, for example silicone, that contains themicro particles such that first and second matrixes 1970, 1975 aresubstantially saturated with the therapeutic agent while the therapeuticagent is released from the core.

First and second drug cores 1910, 1915 are surrounded by a sheath body1920, except at an exposed surface where the therapeutic agents arereleased, in this case at the proximal end 1912. Sheath body 1920 issubstantially impermeable to the first and second therapeutic agents, sothat the first and second therapeutic agents are released from theexposed surface on the open end of first and second drug cores 1910,1915 that are not covered with sheath body 1920. In some embodiments,the implant may be incorporated into a different structure, such as apunctal plug.

FIG. 19B shows a side cross sectional view of the sustained releaseimplant of FIG. 19A. First drug core 1910 with the first therapeuticagent is a cylindrical shaped structure and shown with a circularcross-section. Second drug core 1915 with the second therapeutic agentis also a cylindrical shaped structure and shown with a circularcross-section. First and second drug cores 1910, 1915 may have differentdiameters or the same diameter, as shown in the figures. Sheath body1920 comprises an annular portion disposed around first and second drugcores 1910, 1915.

FIG. 20A shows a cross sectional view of a sustained release implant2000 having therapeutic agents to treat an eye, according to embodimentsof the present invention. Implant 2000 has a proximal end 2012 and adistal end 2014. Implant 2000 includes two concentric drug cores 2010,2015 with hollow centers to allow fluid flow through the implant 2000.First drug core 2010 is a hollow cylindrical shaped structure thatincludes a first therapeutic agent and second drug core 2015 is a hollowcylindrical shaped structure that includes a second therapeutic agent.Second drug core 2015 is configured to fit within a central opening offirst drug core 2010, as shown in the figures. First and second drugcores 2010, 2015 may have the same length, or different lengths, asshown in the figures. First drug core 2010 comprises a first matrix 2070that contains first inclusions 2060 of the first therapeutic agent andsecond drug core 2015 comprises a second matrix 2075 that containssecond inclusions 2065 of the second therapeutic agent. First and secondinclusions 2060, 2065 will often comprise a concentrated form of thefirst and second therapeutic agents, for example a liquid or solid formof the therapeutic agents, and the therapeutic agents may over timedissolve into a first matrix 2070 of first drug core 2010 and a secondmatrix 2075 of second drug core 2015, respectively. First and secondmatrixes 2070, 2075 can comprise a silicone matrix or the like, and themixture of therapeutic agents within matrixes can be non-homogeneous. Inmany embodiments, the non-homogenous mixture comprises a silicone matrixportion that is saturated with the therapeutic agents and an inclusionsportion comprising inclusions of the therapeutic agents, such that thenon-homogenous mixture comprises a multiphase non-homogenous mixture.The first matrix may differ from the second matrix, including, forexample, an exposed surface area, a surfactant, a cross-linking, anadditive, and/or matrix materials including formulation and/orsolubility. In some embodiments, first and second inclusions 2060, 2065comprise droplets of an oil of the therapeutic agent, for examplelatanoprost oil. In some embodiments, inclusions may comprise particlesof the therapeutic agent, for example solid bimatoprost particles. Firstand second inclusions 2060, 2065 may comprise microparticles havingdimensions from about 0.1 μm to about 100 μm, or about 200 μm. Thecontained inclusions at least partially dissolve into the surroundingsolid matrix, for example silicone, that contains the micro particlessuch that first and second matrixes 2070, 2075 are substantiallysaturated with the therapeutic agent while the therapeutic agent isreleased from the core.

First drug core 2010 is surrounded on its outer surface by a sheath body2020, having first drug core 2010 with an open inner surface 2085 andexposed proximal and distal end surfaces. Sheath body 2020 issubstantially impermeable to the first therapeutic agents in first drugcore 2010, so that the first therapeutic agents are released from theexposed surfaces of the drug core 2010. Second drug core 2015 issurrounded on its outer surface by first drug core 2010, with an openinner surface 2080 and exposed proximal and distal end surfaces. Thesecond drug core 2015 is shorter than the first drug core 2010 so thatportions of the inner surface 2085 are exposed. First therapeutic agentsare released from the exposed surfaces of first drug core 2010 that arenot covered by the sheath body 2020 and second drug core 2015, andsecond therapeutic agents are released from the exposed surfaces ofsecond drug core 2015 that are not covered with first drug core 2010. Insome embodiments, the implant may be incorporated into a differentstructure, such as a punctal plug.

FIG. 20B shows a side cross sectional view of the sustained releaseimplant of FIG. 20A with concentric drug cores. First drug core 510 withthe first therapeutic agent is shown with a circular cross-section witha first open center portion. Second drug core 2015 with the secondtherapeutic agent is shown with a circular cross-section with a secondopen center and is configured to fit within the first open centerportion of first drug core 2010, while allowing flow through the centerof the second drug core 2015, as shown in the figures. Sheath body 2020comprises an annular portion disposed on first drug core 2010.

The drug cores disclosed above comprise the first and second therapeuticagents and materials to provide sustained release of the first andsecond therapeutic agents. The first and second therapeutic agentsmigrate from the drug core to the target tissue, for example ciliarybody of the eye. The ocular surface could be targeted for cyclosporine A(control inflammation) and mucin inducers for dry eyes. The uvea couldbe targeted by steroids, NSAIDs and CSA for uveitis. The first andsecond therapeutic agents may optionally be only slightly soluble in thematrix so that the release rate remains “zero order” for the lifetime ofthe release of the first and second therapeutic agents when dissolved inthe matrix and available for release from the exposed surfaces of thedrug cores. As the first and second therapeutic agents differs from theexposed surfaces of the drug cores to the tear or tear film, the rate ofmigration from the drug cores to the tear or tear film is related to theconcentration of first and second therapeutic agents dissolved in thematrixes. In some embodiments, the concentration of first and secondtherapeutic agents dissolved in the drug cores may be controlled toprovide the desired rate of release of the first and second therapeuticagents. In some embodiments the desired rate of release of the firsttherapeutic agent may be the same as the desired rate of release of thesecond therapeutic agent. In some embodiments the desired rate ofrelease of the first therapeutic agent may be different than the desiredrate of release of the second therapeutic agent. The first and secondtherapeutic agents included in the drug cores can include liquid, solid,solid gel, solid crystalline, solid amorphous, solid particulate, and/ordissolved forms of the therapeutic agents. In some embodiments, the drugcores comprise a silicone matrix containing the first and secondtherapeutic agents.

The drug cores can be made from any biocompatible material capable ofproviding a sustained release of the therapeutic agents. Although thedrug cores are described above with respect to embodiments comprising amatrix with a substantially non-biodegradable silicone matrix withparticles of the drugs located therein that at least partially dissolve,the drug cores can include any structure that provides sustained releaseof the first and second therapeutic agents, for example biodegradablematrix, a porous drug core, liquid drug cores and solid drug cores. Insome embodiments, the drug cores have the same structure, while in otherembodiments, the drugs cores have different structures. The structurescan be adapted to release the first and second therapeutic agents intherapeutic amounts over a period of time from about one to twelvemonths after the structure is inserted into the eye. In some embodimentsthe release rate for the first and second therapeutic agents may be thesame or similar. In other embodiments the release rate for the first andsecond therapeutic agents may be different, with one therapeutic agentbeing released at a higher rate than the other therapeutic agent. Amatrix that contains the first and second therapeutic agents can beformed from either biodegradable or non-biodegradable polymers. Examplesof biodegradable polymers may include poly(L,-lactic acid) (PLLA),poly(L-glycolic acid) (PLGA), polyglycolide, poly-L-lactide,poly-D-lactide, poly(amino acids), polydioxanone, polycaprolactone,polygluconate, polylactic acid-polyethylene oxidc copolymers, modifiedcellulose, collagen, polyorthoesters, polyhydroxybutyrate,polyanhydride, polyphosphoester, poly(alpha-hydroxy acid), collagenmatrices and combinations thereof. The devices of the present inventionmay be fully or partially biodegradable or non-biodegradable. Examplesof non-biodegradable materials are various commercially availablebiocompatible polymers including but not limited to silicone,polyethylene terephthalate, acrylates, polyethylenes, polyolefins,including ultra high molecular weight polyethylene, expandedpolytetrafloroethylene, polypropylene, polycarbonate urethane,polyurethanes, polyamides, sheathed collagen. Additional examples ofpolymers may include cyclodextrans, chitans, hyaluronic acid,chrondroitin sulfate and any cross limited derivatives of thesepolymers. In some embodiments the drug cores may comprise a hydrogelpolymer, either degradable or non-degradable. In some embodiments, thetherapeutic agents can be comprised in a drug eluting material used as acoating, such as those commercially available from Surmodics of EdenPrairie, Minn., and Angiotech Pharmaceuticals of British Columbia,Canada, and the like.

The first and second therapeutic agents can comprise any substance, forexample a drug, that effects the eye. In some embodiments, the first andsecond therapeutic agents work together in treating the eye. In otherembodiments, the first therapeutic agent can counteract possible sideeffects of the second therapeutic agent. The additional counteractivetherapeutic agent can be comprised within the core that releases thetherapeutic agent that treats the eye, such as shown in FIG. 2A, orseparate drug cores can be provided to separately release the additionalcounteractive therapeutic agent, such as shown in FIGS. 3A, 4A and 5A.

For example, one possible side effect of a cycloplegic therapeutic agentis pupil dilation that can result in photophobia. Therefore, a miotictherapeutic agent is released into the eye to counteract the pupildilation caused by the cycloplegic. Cycloplegic therapeutic agents mayinclude atropine, cyclopentolate, succinylcholine, homatropine,scopolamine, and tropicamide. Miotic therapeutic agents may includeechothiophate, pilocarpine, physostigmine salicylate,diisopropylfluorophosphate, carbachol, methacholine, bethanechol,epinephrine, dipivefrin, neostigmine, echothiopateiodide and demeciumbromide. Other suitable therapeutic agents include mydriatics such ashydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine,cyclopentolate, oxyphenonium and eucatropine. In addition,anti-cholinergics may be employed such as, pirenzepine. Examples ofapplicable therapeutic agents may be found in U.S. Patent ApplicationPublication Nos. 2006/0188576 and 2003/0096831, hereby incorporated byreference in their entirety.

Another potential side effect of cycloplegic therapeutic agents isglaucoma, possibly related to the dilation of the pupil. Therefore, thesecond therapeutic agent is an anti-glaucoma agent released tocounteract a possible glaucoma inducing side effect of the firsttherapeutic agent used to treat the eye. Suitable anti-glaucomatherapeutic agents include: sympathomimetics such as Apraclonidine,Brimonidine, Clonidine, Dipivefrine, and Epinephrine;parasympathomimetics such as Aceclidine, Acetylcholine, Carbachol,Demecarium, Echothiophate, Fluostigmine, Neostigmine, Paraoxon,Physostigmine, and Pilocarpine; carbonic anhydrase inhibitors such asAcetazolamide, Brinzolamide, Diclofenamide, Dorzolamide, andMethazolamide, beta blocking agents such as Befunolol, Betaxolol,Carteolol, Levobunolol, Metipranolol, and Timolol; prostaglandinanalogues such as Bimatoprost, Latanoprost, Travoprost, and Unoprostone;and other agents such as Dapiprazole, and Guanethidine. In a preferredembodiment, atropine is released as a first therapeutic agent to treatdevelopmental myopia in children, and bimatoprost and/or latanoprost isreleased as a second therapeutic agent for anti-glaucoma treatment.

Other non-limiting examples of the active agents or medications whichare appropriate for use with the invention include, for example only:topical prostaglandin derivatives such as latanoprost, travaprost andbimatoprost used for the topical treatment of glaucoma. Also a treatmentfor corneal infections is appropriate using ciprofloxacin, moxifloxacinor gatifloxacin. Systemic medications useful for this invention arethose used for hypertension such as atenolol, nifedipine orhydrochlorothiazide. Any other chronic disease requiring chronicmedication could be used. The active agents or medications may byantiinfective agents. For example for bacteria use fluoroquinolones, βlactan, aminoglycosides or cephalasporins. For antiviral agents useantimycotics. For anti-inflammatory agents use gluco corticoid steroid,NSAIDs and other analgesics.

The treatment of allergic conjunctivitis and rhinitis are alsoapplications for the invention, e.g. using antihistamine andanti-allergy medication such as olopatadine and cromalyn sodium in or onthe implant.

This list of active agents is not comprehensive in that many otheragents can be used with the present invention. For example, a treatmentfor dry eye by topical cyclosporin is particularly interesting foradministration by the present invention, in which a therapeutic amountof cyclosporin may be delivered each day that is less than the dailydrop administered quantity, for example, the therapeutic amount may be 5to 10% of the drop administered quantity of cyclosporin or Restasis®,commercially available from Allergan. There are many other active agentscan also be administered using the method and apparatus of theinvention. The active agents may be lubricants and emollients like PVA,PVP, modified cellulose molecules like carboxymethyl cellulose andhydroxypropyl methyl cellulose, also Hyaluronic acid and mucinstiulators.

It should be noted that some therapeutic agents will have more than oneeffect on the eye. For example, anti-glaucoma therapeutic agents canalso cause pupil constriction. Thus in some embodiments, the secondtherapeutic agent can counteract more than one side effect of the firsttherapeutic agent that is released to treat the eye.

The first and second therapeutic agents are released at therapeuticlevels to provide a desired treatment response when the implantsdisclosed above are implanted in a tissue or near the eye. The first andsecond therapeutic agents are preferably released at a uniform rate, forexample a rate that corresponds to zero order kinetics, although thetherapeutic agents can be released at rates that correspond to otherorders of reaction kinetics, for example first order. In manyembodiments, the kinetic order of the reaction will vary from zero orderto first order as the first and second therapeutic agents are released.Thus, the first and second therapeutic agents are released with aprofile that corresponds to a range of kinetic orders that varies fromabout zero to about one. Ideally, the drug cores are removed before therate at which the first and second therapeutic agents are releasedchanges significantly so as to provide uniform delivery of the first andsecond therapeutic agents. As a uniform rate of delivery is desired, itmay be desirable to remove and/or replace the drug cores before thereaction kinetics transition entirely to first order. In otherembodiments, first or higher order release kinetics may be desirableduring some or all of the treatment, so long as the first and secondtherapeutic agents release profile remains within a safe and effectiverange. In some embodiments the drug cores may release first and secondtherapeutic agents at an effective rate for the period of 1 week to 5years, more particularly in the range of 3-24 months. As pointed outabove, in some embodiments it may be desirable for the drugs cores tohave similar release rates for the first and second therapeutic agents.In other embodiments, it may be desirable for the drug cores to havedifferent release rates for the first and second therapeutic agents,depending on the therapeutic agents used.

The rate of release of the first and second therapeutic agents can berelated to the concentration of first and second therapeutic agentsdissolved in the drug cores. In many embodiments, the drug corescomprise additional non-therapeutic agents that are selected to providea desired solubility of the first and second therapeutic agents in thedrug cores. The non-therapeutic agent of the drug cores can comprisepolymers as described above and additives. A polymer of the drug corecan be selected to provide the desired solubility of the first andsecond therapeutic agents in the matrix. For example, the drug core cancomprise hydrogel that may promote solubility of hydrophilic treatmentagents. In some embodiments, functional groups can be added to thepolymer to modulate the release kinetics of one or both of thetherapeutic agents. For example, functional groups can be attached tosilicone polymer. In some embodiments different ions may generatedifferent salts with different solubility.

In some embodiments, additives may be used to control the concentrationof the first and second therapeutic agents by increasing or decreasingsolubility of the therapeutic agents in the drug cores. The solubilitymay be controlled by providing appropriate molecules and/or substancesthat increase and/or decrease the solubility of the dissolved form ofthe therapeutic agents to the matrixes. The solubility of the dissolvedform of the therapeutic agents may be related to the hydrophobic and/orhydrophilic properties of the matrix and therapeutic agents. Forexample, surfactants, salts, hydrophilic polymers can be added to thematrix to modulate the release kinetics. In addition, oils andhydrophobic molecules can be added to the matrix to modulate the releasekinetics of the matrix.

Instead of or in addition to controlling the rate of migration based onthe concentration of the first and second therapeutic agents dissolvedin the matrix, the surface area of the drug cores can also be controlledto attain the desired rate of drug migration from the core to the targetsite. For example, a larger exposed surface area of the drug cores willincrease the rate of migration of the first and second therapeuticagents from the drug core to the target site, and a smaller exposedsurface area of the drug core will decrease the rate of migration of thefirst and second therapeutic agents from the drug core to the targetsite. The exposed surface area of the drug cores can be increased in anynumber of ways, for example by making the exposed surface tortuous orporous, thereby increasing the surface area available to the drug cores.

The sheath body of the implants disclosed above comprise appropriateshapes and materials to control migration of the first and secondtherapeutic agents from the drug cores. The sheath body houses the drugcores and can fit snugly against the cores. The sheath body is made froma material that is substantially impermeable to the therapeutic agentsso that the rate of migration of the therapeutic agents may be largelycontrolled by the exposed surface area of the drug cores that are notcovered by the sheath body. Typically, migration of the therapeuticagents through the sheath body will be about one tenth of the migrationof the therapeutic agents through the exposed surface of the drug cores,or less, often being one hundredth or less. In other words, themigration of the therapeutic agents through the sheath body is at leastabout an order of magnitude less that the migration of the therapeuticagents through the exposed surface areas of the drug cores. Suitablesheath body materials include polyimide, polyethylene terephthalate”(hereinafter “PET”). The sheath body has a wall thickness from about0.00025″ to about 0.0015″. The total diameter of the sheath that extendsacross the drug cores range from about 0.2 mm to about 1.2 mm. The drugcores may be formed by dip coating the drugs cores in the sheathmaterial. Alternatively, the sheath body can be a tube and the drugcores introduced into the sheath as a liquid or slid into the sheathbody tube.

The sheath body can be provided with additional features to facilitateclinical use of the implant. For example, the sheath may replaceablereceive drug cores that are exchangeable while the retention element andsheath body remain implanted in the patient. The sheath body is oftenrigidly attached to the retention element as described above, and thedrugs cores are exchangeable while the retention element retains thesheath body. For example, the sheath body can be provided with externalprotrusions that apply force to the sheath body when squeezed and ejectthe drug cores from the sheath body. Another drug core can then bepositioned in the sheath body.

In another embodiment, the therapeutic implant includes an implantablebody that is sized and shaped for insertion into the patient body. Theimplantable body has a first receptacle and a second receptacle. Thefirst receptacle includes a first therapeutic agent and a first surfacefor releasing the first therapeutic agent. The second receptacleincludes a second therapeutic agent and a second surface for releasingthe second therapeutic agent. The first and second therapeutic agentsmay be any therapeutic agent described herein. The first and secondtherapeutic agents may be released at therapeutic levels through thefirst and second surfaces of the first and second receptacles over asustained period when the implant is implanted for use. As disclosedherein, the release rate and/or the release period of the first andsecond therapeutic agents may be the same or different. In otherembodiments, the first and second receptacles be shaped and positionedwithin the sustained release implants and therapeutic implants describedin the present application.

FIG. 2I schematically illustrates one embodiment of a lacrimal insert inthe shape of a punctal plug 2100 for use in a therapeutic implantconfigured to hold a sustained release implant with at least one drugcore containing first and second therapeutic agents. The punctal plug2100 includes a collarette 2110 at a proximal end which rests on theexterior of the punctum 11, 13 (see FIG. 34), a bulb 2120 with a taperedportion 2125 terminating in a tip 2135 at a distal end that blockinglyprojects into the canaliculus 10, 12 (see FIG. 34), and a body portion2130 connecting the collarette 2110 and the bulb 2120. The punctal plug2100 is approximately 2.0 mm in length. The bulb 2120 is designed toprevent the punctal plug 2100 from being easily dislodged from thecanaliculus 10, 12, and may be tapered for ease of insertion into thepunctum 11, 13. The collarette 2110 is designed to have a diameter toprevent the punctal plug 2100 from completely entering the canaliculus10, 12, and is preferably smooth to minimize irritation of the eye. Thebody portions 2130 of the punctual plug 2100 is essentially anon-functional connection between the collarette 2110 and the bulb 2120portions. The collarette 2110 includes an aperture 2140 extending intothe body portion 2130 into which an implant 2145 is placed. The size ofthe aperture 2140 is selected to hold the implant in place duringtreatment. In some embodiments, a sheath body of the implant may beomitted and the drug core(s) may be inserted directly into the aperture2140 of the punctal plug 2100. In some embodiments, the tip 2135 isclosed, in other embodiments, an opening 2150 in the tip 2135 at thedistal end allows access to the aperture 2140, allowing fluid flowthrough the punctal plug. In some embodiments, an optional non-poroushead 2115 is provided over the collarette 2110 to enclose the aperture2140. In accord with one aspect of the invention, the body 2110 and head2115 are made of different materials, with the body 2110 may be moldedor otherwise formed from a flexible material, such as silicone, that isimpermeable to the therapeutic agents, and the head 2115 being made froma biocompatible, preferably soft and flexible second material which ispermeable to the medication. When the punctal plug 2100 is in place, thetherapeutic agents are deployed from the drug core(s) into the tears ofthe lacrimal lake where the therapeutic agents mix, as eye drops do,with the tears and penetrates the eye to have the intendedpharmacological effect. The size of the aperture 2140 is selected tohold the implant in place during treatment.

FIGS. 22-25 show different embodiments of therapeutic implants having astructure, such as a punctual plug 2100. Other structures suitable forincorporation with the present invention are described in U.S. Pat. App.Pub. Nos. 2006/0020253, entitled “Implantable device having controlledrelease of medication and method of manufacturing the same”, publishedin the name of Prescott on Jan. 26, 2006; and U.S. Pat. No. 7,117,870,entitled “Lacrimal insert having reservoir with controlled release ofmedication and method of manufacturing the same”, issued on Oct. 10,2006 in the name of Prescott, the full disclosures of which areincorporated herein by reference. The reservoir can include any of thetherapeutic agents described herein to treat the eye, for examplemedications to treat optical defects of the eye.

FIG. 22 schematically illustrates one embodiment of a therapeuticimplant 2200 having a punctal plug 2100 and a sustained release implantcontaining first and second therapeutic agents. In the embodiment shown,the sustained release implant is sustained release implant 2200discussed above having drug core 2210 with first inclusions 2260 of afirst therapeutic agent and second inclusions 2265 of a secondtherapeutic agent. This embodiment of the therapeutic implant 2200further includes the optional head 2115 at a proximal end that ispermeable to the first and second therapeutic agents. When thetherapeutic implant 2200 is in place, the first and second therapeuticagents are deployed from proximal end of the drug core through thepermeable head into the tears of the lacrimal lake where the first andsecond therapeutic agents mix, as eye drops do, with the tears andpenetrates the eye to have the intended pharmacological effect. The sizeof the aperture 2240 is selected to hold the sustained release implantin place during treatment. In the embodiment shown, the sheath body isalso within the aperture 2140. In other embodiments, the sheath body2220 may be omitted and the drug core 2210 may be inserted directly intothe aperture 2140 of the punctal plug 2100.

FIG. 23 schematically illustrates one embodiment of a therapeuticimplant 2300 having a punctal plug 2100 and a sustained release implanthaving first and second concentric drug cores with first and secondtherapeutic agents. In the embodiment shown, the sustained releaseimplant is sustained release implant 2300 having an outer first drugcore 2310 with first inclusions 2360 of a first therapeutic agent and aninner second drug core 2315 with second inclusions 2365 of a secondtherapeutic agent. When the therapeutic implant 2300 is in place, thefirst and second therapeutic agents are deployed from the drug cores atthe exposed or proximal end and into the tears of the lacrimal lakewhere the first and second therapeutic agents mix, as eye drops do, withthe tears and penetrates the eye to have the intended pharmacologicaleffect. The size of the aperture 2140 is selected to hold the sustainedrelease implant in place during treatment. In some embodiments, thesheath body 2320 of the implant 2300 may be omitted and the first andsecond drug cores 2310, 2315 may be inserted directly into the aperture2140 of the punctal plug 2100. Optionally, a head 2115 may be used thatis permeable to the first and second therapeutic agents, wherein firstand second therapeutic agents are deployed from first and second drugcores 2310, 2315 through permeable head 2115.

FIG. 24 schematically illustrates one embodiment of a therapeuticimplant 2400 having a punctal plug 2100 and a sustained release implanthaving first and second drug cores containing first and secondtherapeutic agents. In the embodiment shown, the sustained releaseimplant is sustained release implant 2400 having a first drug core 2410with first inclusions 2460 of a first therapeutic agent next to a seconddrug core 2415 with second inclusions 2465 of a second therapeuticagent. When the therapeutic implant 2400 is in place, the first andsecond therapeutic agents are deployed from the drug cores at theexposed or proximal ends and into the tears of the lacrimal lake wherethe first and second therapeutic agents mix, as eye drops do, with thetears and penetrates the eye to have the intended pharmacologicaleffect. The size of the aperture 2140 is selected to hold the implant2400 in place during treatment. In some embodiments, the sheath body2420 of the implant 400 may be omitted and the first and second drugcores 2410, 2415 may be inserted directly into the aperture 2140 of thepunctal plug 2100. Optionally, a head 2115 may be used that is permeableto the first and second therapeutic agents, wherein first and secondtherapeutic agents are deployed from the first and second drug cores2410, 2415 through the permeable head 2115.

FIG. 25 schematically illustrates one embodiment of a therapeuticimplant 2500 having a punctal plug 2100 and a sustained release implanthaving first and second concentric drug cores in a flow-throughconfiguration, with each drug core containing a therapeutic agent. Inthe embodiment shown, the sustained release implant is sustained releaseimplant 2500 having an outer first drug core 2510 with first inclusions2560 of a first therapeutic agent and an inner second drug core2515 withsecond inclusions 2565 of a second therapeutic agent. In the embodimentshown, the punctal plug 2100 includes an opening 2150 in the tip 2135 atthe distal end allowing fluid flow through the body of the punctal plug2100 from the proximal end to the distal end and through first andsecond drug cores 2510, 2515. When the therapeutic implant 2500 is inplace, the first and second therapeutic agents are deployed from thedrug cores 2510, 2515 at the exposed ends and exposed inner surfaces2585, 2580 as the fluid flows through. The size of the aperture 2140 ofthe punctal plug 2100 is selected to hold the implant in place duringtreatment and the opening 2150 is sized to allow sufficient flow throughthe implant 2100 and first and second drug cores 2510, 2515. In someembodiments, the sheath body of the implant may be omitted and first andsecond drug cores 510, 2515 may be inserted directly into the aperture2140 of the punctal plug 2100. Optionally, a head 2115 may be used thatis permeable to the first and second therapeutic agents. Otherflow-through structures suitable for incorporation with the presentinvention are described in U.S. patent application Ser. No. 11/695,545,entitled “Nasolacrimal Drainage System Implants for Drug Therapy, filedApr. 2, 2007, and issued as U.S. Pat. No. 7,998,497 on Aug. 16, 2011,the full disclosure of which is incorporated herein by reference.

FIGS. 26A-26C show therapeutic implants 2600, 2600′, 2600″ thatencompass punctual plugs and structures that release first and secondtherapeutic agents, according to an embodiment of the present invention.Structures suitable for incorporation with the present invention aredescribed in U.S. Pat. No. 3,949,750, entitled “Punctum plug and methodfor treating keratoconjunctivitis sicca and other ophthalmic alimentsusing same”, issued in the name of Freeman on Apr. 13, 1976, the fulldisclosure of which is incorporated herein by reference. The headportion can include any two of the therapeutic agents described hereinto treat the eye.

In the treatment of ophthalmic ailments where it is desired to preventor decrease the drainage of lacrimal fluid and/or medication from theeye, the punctal aperture in one or both of the upper and lower lids areto be blocked by therapeutic implants, two respective embodiments ofwhich are shown in FIGS. 26A and 26B. Referring initially to theembodiment of FIG. 26A, the therapeutic implant 2600 has a blunted tipor barb portion 2620 at a distal end, a middle neck or waist portion26130 of somewhat smaller diameter than the tip, and a smooth disc-likehead portion 2610 at a proximal end of relatively larger diameter. Thetherapeutic implant 2600′ of FIG. 26B is of generally similar dimensionsto the first-described embodiment with a blunted tip or barb portion2620′, a cylindrical middle portion 2630′ of substantially the samedimension, and a dome-shaped head portion 2610′ of somewhat smallerdiameter than its counterpart in the embodiment of FIG. 26A. The headportion 2610, 2610′ of both embodiments may be provided, if desired asan alternative to grasping it with forceps, with a central bore opening2640, 2640′ adapted to receive the projecting tip of an inserter tool toprovide a releasable grip on the therapeutic implant as it ismanipulated for insertion, as hereinafter described.

FIG. 26C shows a hollow therapeutic implant 2600″ that is of generallysimilar dimensions to the first-described embodiment having a bluntedtip or barb portion 2620″, a middle neck or waist portion 2630″ ofsomewhat smaller diameter than the tip, a smooth disc-like head portion2610″ of relatively larger diameter and a central bore 2640″ extendingthrough the plug. The central bore 2640″ allows fluid flow from aproximal end to distal end of the therapeutic implant 2600″.

In some embodiments of the invention, the two therapeutic agents asdescribed herein are incorporated in a punctal plug as described in U.S.App. Pub. No. 2005/0197614, the full disclosure of which is incorporatedherein by reference. A gel can be used to form the therapeutic implant2600, 2600′, 2600″ and the gel can swell from a first diameter to asecond diameter in which the second diameter is about 50% greater thanthe first diameter. The gel can be used to entrap the first and secondtherapeutic agents, for example within a microporous structure in whichthe agents are uniformly dispersed, and the gel can slowly elute thefirst and second therapeutic agents into the patient. Varioustherapeutic agents have been describe herein and additional therapeuticagents are described in U.S. Provisional Application No. 60/550,132,entitled “Punctum Plugs, Materials, And Devices”, the full disclosure ofwhich is incorporated herein by reference, and may be combined with thegels and devices described herein.

In other embodiments of the invention, the entire body or only portionsof the therapeutic implants 2600, 2600′, 2600″ may be made of amedication-impregnable porous material such as HEMA hydrophilic polymer,or may be otherwise adapted as with capillaries or the like, to storeand slowly dispense ophthalmic drugs to the eye as they are leached outby the lacrimal fluids. For example, the head portion 2610, 2610′, 2610″of each embodiment may be medication-impregnable porous materialimpregnated with first and second therapeutic agents.

FIG. 27 shows therapeutic implants containing first and secondtherapeutic agents as applied to the eye. In the embodiment shown, atherapeutic implant 2700 is designed for insertion into the lowerpunctal aperture 13 of the eye 2, and along the canaliculus 12communicating with the aperture. The therapeutic implant 2700 includes acollarette 2710 at a proximal end, a flared portion 2720 at a distalend, a neck portion 2730. The collarette 2710 is designed for seatingagainst the aperture 13. Examples of suitable therapeutic implants 2700containing two therapeutic agents have been described above, and includetherapeutic implants 2200, 2300, 2400, 2500, 2600, 2600′ and 2600″. Thetherapeutic implant 2700 may be used to block fluid flow, or may have ahollow portion allowing fluid flow. In the embodiment shown in FIG. 27,the therapeutic implant 2700 is shown as being a hollow like a strawshape for the passage of tears. Examples of these include therapeuticimplants 2500 and 2600″. Unlike the tear stopping therapeutic implants2200, 2300, 2400, 2600 and 2600′, the hollow therapeutic implants 2500and 2600″ provide a very different drug administering method, scheme andstructure. The hollow therapeutic implant is particularly useful in thatthe active agents are available at the inner surface or interior of thetherapeutic implant, and is uniquely structured to pass tears and thusadminister the active therapeutic agents to the tear stream in a fashionthat is controlled by the flow of tears which thus act as the carrierfor the therapeutic agents.

FIG. 27 further shows an implant 2700′ containing first and secondtherapeutic agents that is a substantially cylindrical in shape that hasbeen inserted into the upper punctum aperture 11, to block the flow oftears to canaliculus 10, while lowerpunctal plug 2700 passes the tearsto canaliculus 12. Examples of suitable implants 2700′ containing twotherapeutic agents may be any one of the implants disclosed herein, orit may be an occlusive plug of some inert biocompatible material.

The therapeutic implant 2700 and implant 2700′ can be used in anydesired combination, either separately or in combination (shown in FIG.27). For example, implant 2700′ can be positioned in the lowercanaliculus and therapeutic implant 2700 can be positioned in the uppercanaliculus. Alternatively, two of the same therapeutic implants 2700 or2700′ can be positioned in both canaliculi.

FIGS. 28, 29A-29D, 30A, and 30B show embodiments of various drugdelivery core elements for use in a therapeutic implant that can betailored to each individual patient based on their needs. The coreelements of the therapeutic implant are pie slice shaped and can beassembled into cylindrical shaped drug cores with many differentconfigurations with many different therapeutic agents. Doing this canachieve therapeutic implant configurations to maximize individualpatient management. This approach can tailor treatment to use multipletherapeutic agents for disease management. The approach can also tailorthe dose of the therapeutic agent based on the genetic and/orphysiological condition of the patient.

FIG. 28 shows various core elements, or drug cores, that are combinableinto a, for example, cylindrical shaped drug core according toembodiments of the present invention. The drug core need not becylindrical, but a cylindrical drug core is preferred for ease ofmanufacture. Drug core 2810 is a blank core element that does notcontain a therapeutic agent, drug core 2820 contains a therapeutic agent2825 with a concentration X, drug core 2830 contains a therapeutic agent2835 with a concentration Y, and drug core 2840 contains a therapeuticagent 2845 with a concentration Z. The cores and the therapeutic agentsmay be any of the cores and therapeutic agents disclosed herein. Whilethe drug cores are shown as pie slice shaped (sectors), the drug coresare not limited to any particular shape. Since the drug cores 2810,2820, 2830, and 2840, or any combination thereof, together can form aright cylindrical shape, (for example, see FIGS. 29A-D) each drug corein this instance is a right prismatic shape with the particularcross-section, for example, a sector cross-section. The drug cores mayhave many different combinable shapes, for example square, rectangular,oval, jig saw puzzle piece, to name a few.

Each individual drug core comprises a matrix that contains thetherapeutic agent, which can be present as a solid solution, or can bepresent as inclusions. Inclusions will often comprise a concentratedform of the therapeutic agent, for example a crystalline form of thetherapeutic agent, and the therapeutic agent may over time dissolve intomatrix of the drug core. A certain concentration of the agent can bedissolved in the matrix in equilibrium with the inclusions of the agent.The concentration of dissolved agent can be a saturation concentration.The matrix can comprise a silicone matrix, or a polyurethane matrix, orthe like. In many embodiments, the non-homogenous mixture comprises asilicone matrix portion that is saturated with the therapeutic agent andan inclusions portion comprising inclusions of the therapeutic agent,such that the non-homogenous mixture comprises a multiphasenonhomogenous mixture. The first matrix may differ from the secondmatrix, including, for example, an exposed surface area, a surfactant, across-linking, an additive, and/or matrix materials includingformulation and/or solubility. In some embodiments, inclusions comprisedroplets of an oil of the therapeutic agent, for example latanoprostoil. In some embodiments, inclusions may comprise particles of thetherapeutic agent, for example solid bimatoprost particles incrystalline form. In many embodiments, matrix encapsulates inclusions,and inclusions may comprise microparticles have dimensions from about0.1 μto about 100 μm, or about 200 μm. The encapsulated inclusionsdissolve into the surrounding solid matrix, for example silicone, thatencapsulates the micro particles such the matrix is substantiallysaturated with the therapeutic agent while the therapeutic agent isreleased from the core.

FIGS. 29A-29D show different embodiments of a cylindrical shaped drugcore using the core elements of FIG. 28 surrounded by a sheath body2920. Sheath body 2920 is can be substantially impermeable to thetherapeutic agents, so that the therapeutic agents are often releasedfrom an exposed surface on an end of the cylindrical shaped drug corethat is not covered with sheath body 2920. In some embodiments, thesheath body may be omitted and the cylindrical shaped drug core be placedirectly into the implant, such as placement in an aperture of a punctalplug. While only four embodiments are shown for the cylindrical shapeddrug core, any suitable drug cores and therapeutic agents may be used.

FIG. 29A shows one embodiment of a cylindrical shaped drug core 2900assembled using two core elements 2810 (blank cores), one core element2820 and one core element 2830. The cylindrical shaped drug core 2900 isthen able to deliver therapeutic agent 2825 with a concentration X andtherapeutic agent 2835 with a concentration Y.

FIG. 29B shows one embodiment of a cylindrical shaped drug core 2905assembled using one core element 2810 (blank core), one core element2820, one core element 2830 and one core element 2840. The cylindricalshaped drug core 2905 is then able to deliver therapeutic agent 2825with a concentration X, therapeutic agent 2935 with a concentration Yand therapeutic agent 2845 with a concentration Z.

FIG. 29C shows one embodiment of a cylindrical shaped drug core 2910assembled using two core elements 2810 (blank core) and two coreelements 2840. The cylindrical shaped drug core 2910 is then able todeliver two doses therapeutic agent 2845 with a concentration Z.

FIG. 29D shows one embodiment of a cylindrical shaped drug core 2915assembled using four core elements 2840. The cylindrical shaped drugcore 2915 is then able to deliver four doses therapeutic agent 2845 witha concentration Z.

FIGS. 30A and 30B show other embodiments of a cylindrical shaped drugcore assembled from core elements of different shapes. FIG. 30A shows acylindrical shaped drug core 3000 made from two core elements 3010, 3015that are semicircular in shape surrounded by a sheath body 3020. FIG.30B shows a cylindrical shaped drug core 3030 made from three coreelements 3040, 3045 and 3050 surrounded by sheath body 3020. Whileembodiments may include a plurality of core elements of substantiallyeven sizes as shown, other embodiments may include core elements of twoor more differing sizes. For example, a semicircular core element 3010may be combined with two ¼ circular core elements 2830 and 2840. A widevariety of different sizes and uneven shapes may also be combined with avariety of geometries, with or without sheath body material (or othermaterial that is substantially impermeable to one or more of thetherapeutic agents) being disposed between the adjacent drug coreelements. For example, sheets of drug core material (including matrixand an associated agent) may formed separately and stacked or layered,and/or may be formed sequentially by polymerizing the matrix over asubstrate or underlying drug core element sheet. The multi-layered drugcore element sheets could then be cut across the layers to a desireddrug core length and/or width. An end and/or side of the sheet could beexposed in the implanted device, with the exposed end or side of eachlayered drug core element having a surface area dependent on a thicknessof the associated drug core layer or sheet.

FIG. 31 shows a sectional view of a sustained release implant 3100having a first drug core 3110 with a first therapeutic agent 3160 and asecond drug core 3115 with a second therapeutic agent 3165 to treat aneye, the first and second drug cores being in a stacked configuration,according to an embodiment of the present invention.

FIG. 31 shows a cross sectional view of a sustained release implant 3100having two therapeutic agents to treat an eye 2, according toembodiments of the present invention. Implant 3100 has a proximal end3112 in which the therapeutic agents are released and a distal end 3114.Implant 3100 includes two drug cores 3110, 3115. First drug core 3110 isa cylindrical shaped structure that includes a first therapeutic agent,and second drug core 3115 is a cylindrical shaped structure thatincludes a second therapeutic agent. The first drug core 3110 and thesecond drug core 3115 are assembled in a stacked configuration, as shownin the figures, with the first drug core 3110 being positioned near theproximal end 3112. First drug core 3110 comprises a first matrix 3170that contains first inclusions 3160 of the first therapeutic agent, andsecond drug core 3115 comprises a second matrix 3175 that containssecond inclusions 3165 of the second therapeutic agent. First and secondinclusions 3160, 3165 will often comprise a concentrated form of thefirst and second therapeutic agents, for example a liquid or solid formof the therapeutic agents, and the therapeutic agents may over timedissolve into first matrix 3170 of first drug core 3110 and secondmatrix 3175 of second drug core 3115. First and second matrixes 3170,3175 can comprise a silicone matrix or the like, and the mixture oftherapeutic agents within matrixes can be non-homogeneous. In manyembodiments, the non-homogenous mixture comprises a silicone matrixportion that is saturated with the therapeutic agents and an inclusionsportion comprising inclusions of the therapeutic agents, such that thenon-homogenous mixture comprises a multiphase non-homogenous mixture.The first matrix may differ from the second matrix, including, forexample, an exposed surface area, a surfactant, a cross-linking, anadditive, and/or matrix materials including formulation and/orsolubility. In some embodiments, first and second inclusions 3160, 3165comprise droplets of an oil of the therapeutic agent, for examplelatanoprost oil. In some embodiments first and second inclusions 3160,3165 may comprise particles of the therapeutic agents, for example solidbimatoprost particles. In many embodiments, first matrix 3170 containsfirst inclusions 3160 and second matrix 3175 contains second inclusions3165. First and second inclusions 3160, 3165 may comprise microparticleshaving dimensions from about 0.1 μm to about 100 μm, or about 200 μm.The contained inclusions at least partially dissolve into thesurrounding solid matrix, for example silicone, that contain the microparticles such that first and second matrixes 3170, 3175 aresubstantially saturated with the therapeutic agent while the therapeuticagent is released from the core.

First and second drug cores 3110, 3115 are surrounded by a sheath body3120, except at an, exposed surface where the therapeutic agents arereleased, in this case at the proximal end 3112. Sheath body 3120 issubstantially impermeable to the therapeutic agents, so that thetherapeutic agents are released from the exposed surface on the open endof first and second drug cores 3110, 3115 that are not covered withsheath body 3120. In some embodiments, the sheath body is similar tosheath body 3120 disclosed above, and a retention structure and anocclusive element, such as retention element and occlusive element asdiscussed above, may be connected to the sheath body. In otherembodiments, the implant may be incorporated into a different structure,such as a punctal plug (see FIG. 32).

FIG. 32 schematically illustrates one embodiment of a therapeuticimplant 3200 having a punctal plug and a sustained release implanthaving first and second stacked drug cores with first and secondtherapeutic agents. In the embodiment shown, the sustained releaseimplant is sustained release implant 3100 having a proximal first drugcore 3110 with first inclusions 3160 of a first therapeutic agent and adistal second drug core 3115 with second inclusions 3165 of a secondtherapeutic agent. When the therapeutic implant 3200 is in place, thefirst therapeutic agent is deployed from the proximal first drug core atthe exposed or proximal end and into the tears of the lacrimal lakewhere the first therapeutic agent mixes, as eye drops do, with the tearsand penetrates the eye to have the intended pharmacological effect.Subsequent to that, the second therapeutic agent is deployed from thedistal second drug core, through the first drug core to the exposed orproximal end and into the tears of the lacrimal lake where the secondtherapeutic agent mixes, as eye drops do, with the tears and penetratesthe eye to have the intended pharmacological effect. The size of theaperture 2140 is selected to hold the sustained release implant 3100 inplace during treatment. In some embodiments, the sheath body 3120 of theimplant 3100 may be omitted and the first and second drug cores 3110,3115 may be inserted directly into the aperture 2140 of the punctal plug2100. Optionally, a head 2115 may be used, such as shown in FIG. 22,that is permeable to the first and second therapeutic agents, whereinfirst and second therapeutic agents are deployed from first and seconddrug cores 3110, 3115 through permeable head 3115.

In other embodiments, referring to FIG. 33, the multiple drug deliverytherapeutic implants 3310 may be implanted in other portions of a body3300, not just in the punctum, to treat a body condition, as shown inFIG. 33. The therapeutic implants 3310 are sustained release implantswith at least one drug core containing first and second therapeuticagents that is used to delivery multiple drugs to treat other conditionsor diseases other than the eye. Therapeutic implant 3310 may includetherapeutic implants having two or more therapeutic agents released froman exposed surface of core(s), such as the therapeutic implantsdescribed above. The therapeutic implant may be implanted by knownmeans.

The first and second therapeutic agents are released at therapeuticlevels to provide a desired treatment response when the implants areimplanted in a body. The first and second therapeutic agents arepreferably released at therapeutic levels over a sustained period. Insome embodiments the drug cores may release first and second therapeuticagents at an effective rate for the period of 1 week to 5 years, moreparticularly in the range of 3-24 months. In some embodiments it may bedesirable for the drugs cores to have similar release rates for thefirst and second therapeutic agents. In other embodiments, it may bedesirable for the drug cores to have different release rates for thefirst and second therapeutic agents, depending on the therapeutic agentsused. In some embodiments, the therapeutic level is less than a doseadministered quantity or less or 5-10% of the dose administeredquantity, typically being less than 10% and often being 5% or less thanthe dose administered quantity each day for an extended period of days.The dose administered quantity may be the oral dose or may be aninjectable dose.

In use, the therapeutic implant 3310 is implanted in the body 3300,where a body fluid may contact the exposed surface of the drug core(s),releasing the first and second therapeutic agents. Depending on theimplant location, any body fluid proximate the therapeutic implant, suchas blood, may contact the exposed surface, releasing the first andsecond therapeutic agents from the implant. The therapeutic implantlocation may include body locations for local drug delivery to joints,such as proximate the shoulder, knee, elbow, or a trauma location 3315,or a trauma location 3320, other locations, such as the abdomen, forgeneral drug delivery. The therapeutic implant 3310 may include one ormore retention elements known in the art to retain the therapeuticimplant 3310 near a body location, such as the body locations listedabove.

In one embodiment, a therapeutic implant may be used in oncology, wherechemotherapy involves use of a cocktail that is dependent upon theprimary tumor type. Use of a local therapeutic implant drug deliverycould allow an extra benefit of treating a tumor site post surgically,and minimizing the collateral damage to the rest of the body. An examplewould be lumpectomy for breast tumor or surgical treatment of prostatecancer, where the therapeutic implant would be implanted near the cancersite. In fact any solid tumor would be a target, with the therapeuticimplant being implanted near the tumor.

In another embodiment, a therapeutic implant may be used for thedelivery of multiple drugs, sometimes called cocktails, for thetreatment of HIV. In this instance, the therapeutic implant would betreating a systemic disease. One example of the multiple drugs in thetherapeutic implant is a protease inhibitor and a nucleic acid target.

Some treatments are contraindicated due to other disease states. Anexample is diabetics where surgeries including amputation are oftenrequired in patients where circulation and wound healing is impaired.The use of steroids could not be used systemically in these patients,but could be used locally. In this embodiment, the therapeutic implantis positioned post surgically in the body at the appropriate locationfor local delivery of a steroid and another drug, such as anantiinflammatory or anti-infective drug. In some embodiments, thesteroid may be released at therapeutic levels for 8 or more weeks andthe anti-inflammatory may be released at therapeutic levels for 2-4weeks.

In joints, non-steroidal anti-inflammatory drugs (NSAIDs) may be usedfor the treatment of such things as osteoarthritis and rheumatoidarthritis. Delivery of NSAIDs locally would reduce the risk associatedwith systemic cox II inhibitors, such as gastrointestinal problems(problems in the stomach or intestine) the may include stomach ulcers orbleeding, and possibly life threatening perforations (rips or holes) inthe wall of the stomach or intestine. In this embodiment, thetherapeutic implant is positioned near the joint to deliver NSAIDslocally and may also include the delivery of a nutritional supplement,like glucosamine, and perhaps get a positive physiological response inlocal tissue.

In another embodiment, a therapeutic implant may be used for localizeddelivery of multiple drugs to a trauma site, such as delivering ananalgesic and an antiinfectives.

FIGS. 34 and 35 show anatomical tissue structures of an eye 2 suitablefor treatment with implants, according to an embodiment of the presentinvention. Eye 2 includes a cornea 4 and an iris 6. A sclera 8 surroundscornea 4 and iris 6 and appears white. A conjunctival layer 9 issubstantially transparent and disposed over sclera 8. A crystalline lens5 is located within the eye. A retina 7 is located near the back of eye2 and is generally sensitive to light. Retina 7 includes a fovea 7F thatprovides high visual acuity and color vision. Cornea 4 and lens 5refract light to form an image on fovea 7F and retina 7. The opticalpower of cornea 4 and lens 5 contribute to the formation of images onfovea 7F and retina 7. The relative locations of cornea 4, lens 5 andfovea 7F are also important to image quality. For example, if the axiallength of eye 2 from cornea 4 to retina 7F is large, eye 2 can bemyopic. Also, during accommodation, lens 5 moves toward cornea 4 toprovide good near vision of objects proximal to the eye.

The anatomical tissue structures shown in FIG. 34 also include thelacrimal system, which includes an upper canaliculus 10 and a lowercanaliculus 12, collectively the canaliculae, and a naso-lacrimal ductor sac 14. The upper canaliculus 10 and lower canaliculus 12 extend fromthe lacrimal sac 14 and terminate in an upper punctum 11 and a lowerpunctum 13, respectively, that also referred to as punctal apertures.The punctal apertures are situated on a slight elevation at the medialend of the lid margin at the junction 15 of the ciliary and lacrimalportions near the medial canthus 17. The punctal apertures are round orslightly ovoid openings surrounded by a connective ring of tissue. Eachcanaliculus extends from punctal openings 11, 13, and comprises avertical position 10v, 12v of the respective canaliculus before turninghorizontally to join its other canaliculus at the entrance of a lacrimalsac 14. The canaliculae are tubular and lined by stratified squamousepithelium surrounded by elastic tissue which permits the canaliculus tobe dilated. The upper and lower canaliculi may each comprise an ampulla10 a, 12 a, or small dilation, in the respective canaliculus.

Manufacture of Implants

FIG. 6A shows a method 600 of manufacturing an implant, according toembodiments of the present invention. A sub method 610 manufactures apunctal plug. A sub method 650 manufactures a drug core insert, forexample as described above. A sub method 690 assembles the componentsinto an integrated drug delivery system.

FIG. 6B shows a method 620 of manufacturing a hydrogel rod for thepunctal plug in accordance with method 600 of FIG. 6A. In someembodiments, method 620 comprises a sub method, or sub-step, of method610. A step 622 combines 40% by weight hydrogel with an organic solvent.In some embodiments, the percentage of hydrogel comprises a range fromabout 5% to about 50% hydrogel, for example from about 20% to about 40%hydrogel. A step 624 mixes the hydrogel with the solvent. In someembodiments, the hydrogel may dissolve in the organic solvent. A step626 injects the hydrogel into a silicone tube. In many embodiments, thesilicone tube is permeable to the organic solvent. The silicone tubecomprises a mold to form the hydrogel. A step 628 cures the hydrogel. Atleast one of a heat or a pressure, in many embodiments both, can be usedto drive off the solvent, for example through the permeable mold, tocure the hydrogel. A step 629 cuts the cured hydrogel to a desiredlength. The curing can be optimized with empirical process/validationstudies with an adequate a sample size, for example 10 sample of curedhydrogels, to determine material variability and/or process variabilityover time. Process variable that can be optimized include time, pressureand temperature of curing. Tolerance analysis associated with theprocess can also be performed.

FIG. 6C shows a method 630 of molding a silicone plug body 637 inaccordance with method 600 of FIG. 6A. A step 632 winds a filamentcomprising a solid material, for example a coil 632C, and heat sets thefilament. A step 634 places the filament comprising heat set coil 632Cin a mold. A step 636 molds plug body 637 with coil 632C embeddedtherein. The plug body may comprise sleeves, tubes, retention structuresand/or at least one chamber as described above. The filament maycomprise at least one of a heat activated material, Nitinol, a shapememory material, a polymer, polypropylene, polyester, nylon, naturalfibers, stainless steel, polymethylmethacrylate or polyimide. In someembodiments, the filament may comprise an absorbable thermoplasticpolymer, for example at least one of polylactic acid (PLA), polyglycolic acid (PGA) or poly-lactic-co-glycolic acid (PLGA). The heatsetting of the filament can be optimized by appropriately controllingthe time and/or temperature of the heat filament based on empirical datafrom a sample of heat set filaments, for example 10 filaments. Themolding of the plug at step 636 can be optimized in several ways, suchas appropriate time and temperature, hard tooling of the mold, amultiple cavity mold, and mold equipment parameters. In someembodiments, a filament for removal of the drug core insert, asdescribed above, can be molded with the plug body such that the filamentis embedded in the plug body and positioned near the channel thatreceives the drug core insert.

FIG. 6D shows a method 640 of assembling the punctal plug components inaccordance with method 600 of in FIG. 6A. Step 630 molds the punctalplug body 637 with a coil 632C. Step 620 molds a hydrogel rod. A step642 inserts the hydrogel rod component into a channel of the plug bodycomponent. A step 644 extends windings of coil 632C over the hydrogelrod. A step 648 dip coats the hydrogel rod and plug body. A step 646 mayprepare a hydrogel coating solution 646 comprising for example a 5%solution of hydrogel by weight. A needle 648N may be placed in a channelof the plug body to hold the body while the hydrogel rod and plug bodyare dipped in the solution.

FIG. 6E shows a method 650 of manufacturing a drug core insert, inaccordance with method 600 of in FIG. 6A. A step 661 prepares a syringeassembly to inject a drug matrix into a polyimide tubing. A step 662prepares a polyimide tubing for injection. A step 670 prepares a drugcore matrix for injection into the tubing. A step 672 injects the drugcore matrix into the polyimide tubing. A step 680 cures the matrixinside the polyimide tubing. A step 682 cuts the polyimide tubing andcured matrix to a length and applies an adhesive.

Step 661 can use known commercially available syringes in the syringeassembly. The syringe assembly may comprise a syringe tube and cartridgeassembly. The syringe tube and cartridge assembly may comprise a tubeattached to a modified needle tip that attaches that attaches to asyringe. The syringe can be connected to a syringe pump or othermechanism to pressurize the tube. The syringe assembly can be used forinjection of the drug core mixture and/or material into the polyimidetubing. In some embodiments, multiple syringes can be used, for examplewith the manufacture of drug inserts that comprise two or- more drugcores. In some embodiments, the syringe assembly may comprise a manifoldwith two or more injection pots that can be used to with separatesyringes in which each syringe includes a different drug core mixture.

Step 662 can prepare the polyimide tubing for injection by attaching a15 cm length of polyimide tubing to a luer. The luer can be connected tothe syringe for injection of the drug core mixture and/or material. Insome embodiments, the tubing connected to the syringe may comprise PMMAand/or PET. In many embodiments the tubing comprises a material thatinhibits release of the therapeutic agent from the drug core through thetubing, for example a material that is substantially impermeable to theflow of the therapeutic agent through the tubing, such that the flow oftherapeutic agent is directed toward the exposed end of the drug core.In some embodiments, for example drug core inserts comprising two ormore concentric drug cores, the tubing may comprise concentric tubes,for example concentric polyimide tubes, with an outer tube arranged toreceive and outer drug core mixture, and an inner tube arranged toreceive an inner drug core mixture. With an annular drug core asdescribed above, concentric tubes may be used to form the annular drugcore, with an inner tube that can be removed after the drug core matrixmaterial has solidified.

In some embodiments, a filament for removal of the drug core insert canbe embedded in the drug core. The filament may be run through thesheath, for example tubing, and the mixture injected into the tubing.The matrix material is then cured with the filament embedded in thematrix.

Step 670 can prepare a drug core mixture comprising a therapeutic agentwith a matrix material, for example silicone. In some embodiments, thetherapeutic agent may comprise at least one of latanoprost, bimatoprostor travoprost. Embodiments can use silicones that comprisedimethylsiloxane, for example Med-4011, Med-6385 and Med-6380 each ofwhich is commercially available from NuSil of Lafayette, Calif. In someembodiments, two or more drug core mixtures are prepared, each forinjection for a separate drug core, for example two mixtures one for aninner drug core and one for an outer drug core.

In a specific embodiment, step 670 can prepare a drug core mixturecomprising inclusions of latanoprost oil in silicone. The therapeuticagent and drug core matrix material can be prepared prior to mixing thetherapeutic agent with the drug core matrix material.

Preparation of Therapeutic Agent

Latanoprost oil can be provided as a 1% solution in methyl acetate. Anappropriate amount of the 1% solution can be placed in a dish. A streamof dry nitrogen can be used to evaporate the solution until only thelatanoprost remains. The dish with latanoprost oil can be placed undervacuum for 30 minutes. In some embodiments, for example those which usebimatoprost available as crystals as the therapeutic agent, theevaporation and vacuum may not be used to prepare the therapeutic agent.

In some embodiments with solid therapeutic agent, for examplebimatoprost crystals, the therapeutic agent can be ground and passedthrough a sieve, prior to mixing with the matrix material. In someembodiments, the sieve may comprise a 120 sieve (125 μm) and/or a 170sieve (90 μm). Work in relation to embodiments of the present inventionindicates that a sieve may remove a very small fraction of therapeuticagent and that many embodiments will work with inclusions of therapeuticagent having a size greater than the optional sieve. In manyembodiments, the release rate is independent of the size and/ordistribution of size of the inclusions, and the release rate can beindependent of particle size for particles from about 0.1 un to about100 μm. In some embodiments, the size and/or distribution of sizes ofthe particles and/or inclusions can be characterized with at least oneof a sieve, light scatter measurements of the core, light microscopy ofthe core, scanning electron microscopy of the core or transmissionelectron microscopy of sections of the core. A sieve can generally beused to create desirable particle sizes and/or exclude undesirableparticle sizes before mixing with the matrix. The exemplary sievecomprises a fine mesh that passes only the desired size particles orsmaller, thereby limiting the therapeutic agent to finer drug particles.This can be used to produce a more homogenous drug core and/or drugparticle size that is easier to mix with the silicone matrix than onewith excessively large particles, although significant variations amongparticle sizes may remain. A variety of sieves may be used. For example,a Sieve # 120 can be used so that the largest particle diameter passedis about 0.0049 inches. Sieve # 170 may pass particles of 0.0035 inchdiameter or smaller. A Sieve # 70 will allow a particle size of 0.0083inch diameter to pass through. Sieves may optionally be used in series.

Preparation of Silicone:

Silicone, for example NuSil 6385, can be obtained from the manufacturerin a sealed container. An appropriate amount of silicone can be weighedbased on the lot size of the build.

Combine Therapeutic Agent with Silicone:

The therapeutic agent, for example latanoprost, can be combined withsilicone, based on the intended and/or measured percentage oftherapeutic agent in the drug core matrix. The percent of latanoprost tosilicone can be determined by the total weight of the drug matrix. Thetherapeutic agent, for example latanoprost, is incorporated into thesilicone by weighing out the appropriate amount of the components. Thefollowing formula can be used to determine the percentage of therapeuticagent in the drug core matrix:

Percent Drug=(weight of drug)/(weight of drug+weight of silicone)×100

For the specific example of latanoprost in silicone the percentage oflatanoprost is silicone is given by:

(20 mg of latanoprost)/(20 mg of latanoprost+80 mg of silicone)×100=20%.

The therapeutic agent, for example latanoprost is combined and mixedwith the silicone using known methods and apparatus for mixingsilicones. In some embodiments, the therapeutic agent comprisinglatanoprost oil may form a micro emulsion comprising inclusions that mayscatter light and appear white.

When a therapeutic agent such as latanoprost, which is in a liquidphysical state at about room temperature (22° C.), and thus is also in aliquid physical state at human body temperature (37° C.), is used, theagent and the matrix material can be mixed by techniques that bringabout a high degree of dispersion of the liquid latanoprost droplets inthe matrix material in which it can be substantially insoluble. Mixingtechniques should provide for a dispersion of the droplet within thematrix material, such that when curing takes place, the liquidtherapeutic agent is present as relatively small, relativelyhomogeneously dispersed discrete droplets within the matrix of solidsilicone material. For example, mixing can include sonication, i.e., theuse of ultrasonic frequencies, such as are generated by an ultrasonicprobe. The probe can be put in contact with the mixture of matrixmaterial and liquid therapeutic agent to prepare an intimate mixture ofthe two substantially immiscible materials. See, for instance, Example12 below.

Step 672 can inject the mixture of therapeutic agent and silicone intothe tubing. A syringe, for example a 1 ml syringe, can be connected tothe syringe tube and cartridge assembly. A drop of catalyst appropriatefor the silicone, for example MED-6385 curing agent, can be placed intothe syringe and the syringe is then filled with the uncured mixture ofsilicone and therapeutic agent, or silicone drug matrix. The mixture,i.e., mixture of the uncured silicone and agent still liquid enough toflow or pump, can be chilled to subambient temperatures. For example,the mixture can be chilled to temperatures of less than 20° C. Forexample, the mixtures can be chilled to 0° C., or to −25° C. Thepolyimide tube is injected with the drug/matrix mixture until the tubeis filled. The tube and associated apparatus can also be chilled tomaintain the subambient temperature of the mixture throughout theprocess of filling or injecting the sheath with the mixture. In variousembodiments, the polyimide tube, or sheath, is filled with the drugmatrix mixture under pressure, for example through use of a highpressure pump. For instance, the drug/matrix mixture, such as can beobtained in mixtures of latanoprost with MED-6385 Part A to whichamounts of catalyst Part B have been added, can be pumped into the tubeunder at least about 40 psi pressure. The tube can be filled at anysuitable rate, but preferably, at rates of less than about 0.5 linearcm/sec. It is believed by the inventors herein that filling the tuberelatively rapidly under a relatively high head of pressure can reducethe degree of phase separation of the substantially immisciblelatanoprost oil and silicone monomer material, such that uponpolymerization (“curing”) to provide the final silicone polymericproduct, the latanoprost droplets are finely dispersed in the solidmatrix in which they are only slightly soluble.

Curing takes place in the presence of the catalyst (“Part B”) of theNuSil MED-6385, and can be carried out at temperatures of at least about40° C., at relative humidity (RH) of at least about 80%, or both. Curingcan be initiated directly after filling the tube and clamping the endsof the filled tube to prevent the formation of voids and loss of theprecursor material from the tube ends.

After curing, which can be complete in about 16-24 hours at 40° C. and80% RH, the clamps can be removed from the ends of the tubing, as thesilicone is fully set up. The tubing can then be cut into sections ofsuitable length for use as drug inserts, for example, lengths of about 1mm.

When the extrusion is carried out at subambient temperatures, small andmore uniform inclusions of the agent can result. For example, when theagent is latanoprost, a liquid at room temperature, extrusion at −5° C.provides significantly smaller and more uniform inclusion droplets. Inan example, cold extrusion yielded a drug core comprising a siliconematrix with latanoprost droplets of average diameter of 6 μm, with astandard deviation of diameter of 2 μm. In comparison, an extrusioncarried out at room temperature yielded a drug core comprising asilicone matrix with latanoprost droplets of average diameter of 19 μm,with a standard deviation of droplet diameter of 19 μm. It is apparentthat the cold extrusion technique provides smaller, more uniforminclusions than does extrusion at room temperature. This in turn resultsin a more uniform concentration of drug throughout the core, or theinsert containing the core, which is desirable for medical applicationsas uniformity of dose is improved.

The open end of the polyimide tube can be closed off until the siliconebegins to solidify. In some embodiments with two or more drug cores, twoor more separate mixtures can each be separately injected from two ormore syringes.

Step 680 cures the drug core matrix comprising the mixture silicone andtherapeutic agent. The silicone is allowed to cure, for example for 12hours. The amount of time and temperature of the cure may be controlled,and empirical data can be generated to determine ideal times andtemperatures of the curing. Work in relation with embodiments of thepresent invention indicates that the silicone material and drug loadingof the core, for example a percentage of therapeutic agent in the core,may effect the optimal time and temperature of the cure. In someembodiments, empirical data can be generated for each silicone matrixmaterial and percentage of each therapeutic agent to determine anoptimal amount of time to cure the injected mixture. In some embodimentswith two or drug cores in a drug core insert, two or more mixtures canbe cured together to cure the drug cores of the insert.

Table 1 shows drug insert silicones that may be used and associated cureproperties, according to embodiments of the present invention. The drugcore insert matrix material can include a base polymer comprisingdimethyl siloxane, such as MED-4011, MED 6385 and MED 6380, each ofwhich is commercially available from the NuSil company. The base polymercan be cured with a cure system such as a platinum-vinyl hydride curesystem and/or a tin-alkoxy cure system, both commercially available fromNuSil. In many embodiments, the cure system may comprise a known curesystem commercially available for a known material, for example a knownplatinum vinyl hydride cure system with known MED-4011. In a specificembodiment shown in Table 1, 90 parts of MED-4011 can be combined with10 parts of the crosslinker, such that the crosslinker comprises 10% ofthe mixture. A mixture with MED-6385 may comprise 2.5% of thecrosslinker, and mixtures of MED-6380 may comprise 2.5% or 5% of thecrosslinker.

TABLE 1 Drug Insert Silicone Selections Crosslinker Curing Material BasePolymer Cure System Percent Properties MED-4011 Dimethyl Platinum  10%Curing inhibited Siloxane vinyl hydride at high Silica filler systemconcentrations material of latanoprost MED-6385 Dimethyl Tin-Alkoxy 2.5%Very slight siloxane inhibition of Diatomaceous curing at high earthfiller concentrations material of latanoprost MED-6380 DimethylTin-Alkoxy 2.5% to 5% Very slight siloxane without inhibition of fillermaterial curing at high concentrations of latanoprost

Work in relation with embodiments of the present invention suggests thatthe cure system and type of silicone material can effect the curingproperties of the solid drug core insert, and may potentially effect theyield of therapeutic agent from the drug core matrix material. Inspecific embodiments, curing of MED-4011 with the platinum vinyl hydridesystem can be inhibited with high concentrations of latanoprost, forexample over 20% latanoprost, such that a solid drug core may not beformed. In specific embodiments, curing of MED-6385 and/or MED 630 withthe tin alkoxy system can be slightly inhibited with highconcentrations, e.g. 20%, of latanoprost. This slight inhibition ofcuring can be compensated by increasing the time and/or temperature ofthe curing process. For example, embodiments of the present inventioncan make drug cores comprising 40% latanoprost and 60% MED-6385 with thetin alkoxy system using appropriate cure times and temperatures. Similarresults can be obtained with the MED-6380 system the tin-alkoxy systemand an appropriate curing time and/or temperature. In many embodiments,the solid drug core forms so as to form a solid structure, for example asolid cylinder, within the drug core that corresponds to the dimensionsof the tube. Even with the excellent results for the tin alkoxy curesystem, work in relation with embodiments of the present inventionsuggests that there may be an upper limit, for example above 50%latanoprost, at which the tin-alkoxy cure system may not produce a soliddrug core. In many embodiments, the therapeutic agent comprises theprostaglandin analogue, for example latanoprost, in the drug solid drugcore may be at least about 5%, for example a range from about 5% to 50%,and can be from about 20% to about 40% by weight of the drug core. Inspecific embodiments with moderate to high loading of the therapeuticagent in the drug core, the drug core may comprise from about 25% toabout 50% of the therapeutic agent in the drug core, for example 50%latanoprost oil in the drug core and/or matrix material.

In some embodiments, the therapeutic agent may comprise a functionalgroup that can, at least potentially, react with the cure system. Insome embodiments, the therapeutic agent may comprise a prostaglandinanalogue such as latanoprost, bimatoprost or travoprost, each of whichmay comprise an unsaturated carbon-carbon double bond that canpotentially react with the platinum vinyl hydride cure system. Theseunsaturated carbon-carbon double bonds can be similar to the vinyl groupin the platinum cure vinyl hydride system, and can potentially reactwith the vinyl hydride cure system via a hydrosilation reaction.Latanoprost comprise an unsaturated carbon-carbon double bond in one ofthe side chains. Bimatoprost and travoprost each comprise twounsaturated carbon-carbon double bonds, one in each side chain. Work inrelation with embodiments of the present invention indicate that thehydrosilation reaction of the unsaturated double bond in theprostaglandin analogues with in the platinum vinyl hydride cure systemdoes not significantly reduce the quantity of prostaglandin analogueavailable for release from the drug core.

In some embodiments, the therapeutic agent may comprise a prostaglandinanalogue such as latanoprost, bimatoprost or travoprost, each of whichmay comprise hydroxyl groups that can potentially react with the tinalkoxy cure system. These hydroxyl groups can potentially react with thealkoxy groups via an alkoxy condensation reaction. Bimatoprost,latanoprost and travoprost each comprise a molecule with three hydroxylgroups that can potentially react via the alkoxy condensation reaction.Work in relation with embodiments of the present invention indicate thatthe alkoxy condensation reaction of the hydroxyl groups in theprostaglandin analogues with in the tin alkoxy cure system does notsignificantly reduce the quantity of prostaglandin analogue availablefor release from the drug core. Work in relation to embodiments of thepresent invention indicates that a negligible amount of therapeuticagent is consumed by solidification or otherwise not available, asextraction data of the therapeutic agent for solid cores shows that atleast 95%, for example 97% or more, of therapeutic agent can beextracted from the drug core.

In some embodiments, the silicone material may comprise an inert fillerto add rigidity to the cured matrix. Work in relation with embodimentsof the present invention suggests that the filler material may increasethe rate of release of the therapeutic agent. The MED-4011 and MED-6385materials are commercially available with the filler material. TheMED-4011 material may comprise an inert silica filler material to addrigidity to the cured silicone matrix. The MED-4385 may comprise inertdiatomaceous earth filler material to add rigidity to the cured siliconematrix.

The inert filler material can increase the concentration of drug in thesilicone of the component matrix as the filler material may notsubstantially absorb the therapeutic agent and the inert filler materialcan reduce the fraction of silicone in the material drug core matrix. Insome embodiments, MED-4385 comprises approximately 25% diatomaceousearth filler and approximately 75% dimethyl siloxane. In a specificembodiment, the drug core may comprise 40% of the therapeutic agent and60% of the material. The 60% of material, e.g. MED-4385, corresponds to45% dimethyl siloxane base polymer and 15% inert diatomaceous earthfiller. Assuming that very little therapeutic agent is absorbed into theinert filler material, the 40% of therapeutic agent is contained withinthe 45% of dimethyl siloxane base polymer, such that the concentrationof therapeutic agent in the base polymer is 47% or about 50%.Consequently, the release rate of the therapeutic agent from the exposedsurface of the silicone drug core insert can be increased slightly asthe concentration of therapeutic agent in the silicone portion of thematrix material can be elevated due to the presence of the fillermaterial. In some embodiments, the drug core may comprise a matrixmaterial without a filler material, such that the therapeutic agent, forexample latanoprost oil, comprises approximately 50% of the material inthe cured solid drug core and may also comprise a concentrationapproximately 50% in the matrix base polymer.

In many embodiments, the size and/or distribution of sizes of theinclusions in the core can be characterized with at least one of lightscatter measurements of the core, light microscopy of the core, scanningelectron microscopy of the core or transmission electron microscopy ofsections of the core.

Step 680 cuts the polyimide tubing with the cured solid matrix mixtureto an intended length and may apply an adhesive to one end of the cutlength of tubing. In many embodiments, the matrix material is cured soas to form a solid drug core structure, for example a cylindrical rodthat corresponds to the shape of the tubing, such that the exposedsurface of the cut solid drug core substantially retains its shape whenimplanted into the patient. In some embodiments with two or more drugcores in a drug core insert, the two or more drug cores can be cuttogether, for example the tubes and cores of concentric drug cores canbe cut together. Cut drug inserts to length:

The polyimide tubing may be inserted into a fixture and cut to a sectionof the specified length. In some embodiments, the cut sections ofpolyimide tubing may be placed in a vacuum for 30 minutes. The cutsection polyimide tubing comprising the drug core insert can beinspected and weighed following the vacuum and the weight may berecorded.

Close Off End of Drug Core Insert:

An adhesive can be applied to one end of the drug core insert. Theadhesive may be applied as a liquid and cured under UV light, forexample cured under UV light for five seconds. In specific embodiments,the adhesive may comprise Loctite 4305 UV adhesive. In many embodimentsthe material applied to one end of the drug core insert comprises amaterial that is substantially impermeable to the therapeutic agent suchthat release of the therapeutic agent through the covered end isinhibited. This inhibition of release from the drug core through thecovered end can result in effective and/or efficient delivery of thedrug through the exposed surface of the drug core on the opposite end,such that the drug is selectively released to the target tissue and/orbodily fluid, for example to the tear liquid tear film. In someembodiments, a filament may be bonded to the end as described above, tofacilitate removal of the drug core insert from the implant.

In some embodiments, the end can be closed by heat welding, pinching thetube end closed, and covering the end of the tube with a cap comprisinga material that is substantially impermeable to the therapeutic agent toinhibit release of the therapeutic agent through the cap. In embodimentswith two or more drug cores in the drug core insert, the covered end maycover both cores, for example cover an inner cylindrical core and anouter annular core.

In some embodiments, with flow of the drug through the drug core, theend of the drug core may not be closed off, or the end may be partiallyclosed, for example with a cap having an opening to let fluid flowthough the channel in the core while the periphery of the cap covers anannular end of the core.

In some embodiments, the exposed end opposite the closed end can beshaped to increase surface area of the exposed end as described above.In some embodiments, a cone with a sharp tip, similar to a sharp penciltip, can be inserted into the exposed surface to indent the exposedsurface with an inverted cone shape that increases surface area. In someembodiments, the exposed end may be crimped to decrease the surfacearea.

FIG. 6F shows method 690 of final assembly in accordance with method 600of FIG. 6A. A step 692 inserts a drug core component into a channel inthe punctal plug. A step 694 packages the punctal plug with the drugcore insert in the channel. A step 696 sterilizes the packaged plug anddrug core insert. A step 698 releases the product.

Step 692 inserts the drug core into the implant, for example a punctualplug. The drug core can be inspected prior to insertion and may be partof the step of insertion. The inspection can comprise visual inspectionto ensure that the sleeve comprising the cut tubing is completely filledwith no voids or foreign particles in the silicone matrix, that thesilicone is flush and the same length as the polyimide tube, that theadhesive comprising cyanoacrylate completely covers one end of the tube,and that the tube is the correct length. The drug insert and implantcomprising the punctual plug can be loaded into a drug insertion tooland holding fixture. The drug insert can be loaded into the implantbore, or channel, using the plunger on the drug insertion tool. The druginsert insertion tool can be removed. The implant comprising the punctumplug can be inspected to verify that the drug core insert is fullyseated in the bore, that the drug core insert is below the surface ofthe punctual plug flange, and that there is no visible damage to theimplant/drug core assembly.

Step 694 packages the punctual plug with the drug core inserted into thechannel. The punctual plug may be packaged with known packaging andmethods, for example with an inner pouch, an outer Mylar pouch, a pouchsealer, argon gas, and an inflation needle. In specific embodiments, twocompleted drug delivery systems, each comprising the punctual plugimplant with drug core insert, are placed in the inner pouch and sealedin the inner pouch. The sealed inner pouch is placed in an outer pouch.The outer pouch may extend about ¼ beyond a pouch sealer element. Thenumber 25 gauge needle can be inserted into the pouch and under thesealing element with the Argon flowing. The sealer element can beclamped and the package allowed to inflate. The argon flow needle can beremoved and the sealing operation repeated. The package can be inspectedby pressing gently on the argon filled pouch to check for leaks. If aleak is detected, the inner pouch can be removed and repacked in a newMylar outer pouch.

Step 696 can sterilize the packaged plug and drug core insert with knownsterilization methods, for example with commercially available e-beamfrom Nutek Corporation of Hayward, Calif.

Step 698 can release the product in accordance with final testing andrelease procedures.

It should be appreciated that the specific steps illustrated in FIGS. 6Ato 6E provide a particular method of manufacturing a plug with a drugcore insert, according to some embodiments of the present invention.Other sequences of steps may also be performed according to alternativeembodiments. For example, alternative embodiments of the presentinvention may perform the steps outlined above in a different order.Moreover, the individual steps illustrated in FIGS. 6A to 6E may includemultiple sub-steps that may be performed in various sequences asappropriate to the individual step. Furthermore, additional steps may beadded or removed depending on the particular applications. One ofordinary skill in the art would recognize many variations,modifications, and alternatives.

EXAMPLES Example 1 Latanoprost Drug Core Elution Data

Drug cores as described above have been fabricated with different crosssectional sizes of 0.006 inches, 0.012 inches, and 0.025 inches, anddrug concentrations of 5%, 10% and 20% in a silicone matrix. Theses drugcores can be made with a Syringe Tube and Cartridge Assembly, MixingLatanoprost with Silicone, and Injecting the mixture into a polyimidetube which is cut to desired lengths and sealed. The length of the drugcores were approximately 0.80 to 0.95 mm, which for a diameter of 0.012inches (0.32 mm) corresponds to total Latanoprost content in the drugcores of approximately 3.5 μg, 7 μg and 14 μg for concentrations of 5%,10% and 20%, respectively.

Syringe Tube and Cartridge Assembly. 1. Take polyimide tubing of threedifferent diameters 0.006 inches, 0.0125 inches and 0.025 inches. 2. Cutpolyimide tubing of different diameters to ˜15 cm length. 3. InsertPolyimide tubes into a Syringe Adapter. 4. Adhesive bond polyimide tubeinto luer adapter (Loctite, low viscosity UV cure). 5. Trim end ofassembly. 6. Clean the cartridge assembly using distilled water and thenwith methanol and dry it in oven at 600 μC.

Mix Latanoprost with Silicone. Prepare Latanoprost. Latanoprost isprovided as a 1% solution in methylacetate. Place the appropriate amountof solution into a dish and using a nitrogen stream, evaporate thesolution until only the Latanoprost remains. Place the dish with theLatanoprost oil under vacuum for 30 minutes. Combine Latanoprost withsilicone. Prepare three different concentrations of Latanoprost (5%, 10%and 20%) in silicone Nusil 6385 and inject it into tubing of differentdiameters (0.006 in, 0.012 in and 0.025 inches) to generate 3 × 3matrixes. The percent of Latanoprost to silicone is determined by thetotal weight of the drug matrix. Calculation: Weight ofLatanoprost/(weight of Latanoprost+weight of silicone)×100=percent drug.

Inject tube. 1. Insert Cartridge and Polyimide tubes assembly into lmlsyringe. 2. Add one drop of catalyst, (MED-6385 Curing Agent) in thesyringe. 3. Force excess catalyst out of the polyimide tube with cleanair. 4. Fill syringe with silicone drug matrix. 5. Inject tube with drugmatrix until the tube is filled or the syringe plunger becomes toodifficult to push. 6. Close off the distal end of the polyimide tube andmaintain pressure until the silicone begins to solidify. 7. Allow tocure at room temperature for 12 hours. 8. Place under vacuum for 30minutes. 9. Place tube in right size trim fixture (prepared in house tohold different size tubing) and cut drug inserts to length (0.80-0.95mm).

Testing. Elution study (in vitro). 1. Place 10 plugs of same size andsame concentration per centrifuge tube and add 1.5 ml of 7.4 pH buffersolution to it. 2. Change the solvent with fresh 7.4 pH buffer afterappropriate time. 3. Take HPLC of the elutant at 210 nm with PDAdetector 2996 using Sunfire C18, 3 mm×10 mm column (Waters Corporation,Milford, Mass.). Acetonitrile and water mixture is used for gradientelution. Calibration was done in house before and after each analysis,using in-house standards with precisely weighed concentration ofLatanoprost. 4. Calculate the amount of drug release per day per devicefor different size tubings having different concentrations ofLatanoprost. 5. Plot elution rate vs area and concentration for day 1and day 14.

FIGS. 7A and 7B show elution data of Latanoprost at day 1 and day 14,respectively, for the three core diameters of 0.006, 0.012 and 0.025inches and three Latanoprost concentrations of approximately 5%, 11% and18%. Elution rate of the Latanoprost in nanograms (ng) per day isplotted versus percent concentration. These data show that the rate ofelution is mildly dependent on the concentration and strongly dependenton the exposed surface area at both time periods. At day 1, the 0.006inch, 0.012 inch and 0.025 inch diameter cores released about 200 ng,400 ng and 1200 ng of Latanoprost, respectively, showing that thequantity of Latanoprost released increases with an increased size of theexposed surface area of the drug core. For each tube diameter, thequantity of Latanoprost released is compared to the concentration ofdrug in the drug core with a least square regression line. For the0.006, 0.012 and 0.025 inch drug cores the slope of the regression linesare 11.8, 7.4 and 23.4, respectively. These values indicate that adoubling of concentration of the Latanoprost drug in the core does notlead to a doubling of the elution rate of the Latanoprost from the core,consistent with droplets of Latanoprost suspended in a drug core matrixand substantial saturation of the drug core matrix with Latanoprostdissolved therein, as described above.

At day 14, the 0.006 inch, 0.012 inch (0.32 mm) and 0.025 inch diametercores released about 25 ng, 100 ng and 300 ng of Latanoprost,respectively, showing that the quantity of Latanoprost releasedincreases with an increased size of the exposed surface area of the drugcore at extended periods of time, and that the quantity of Latanoprostreleased is mildly dependent on the concentration of therapeutic agentin the core. For each tube diameter, the quantity of Latanoprostreleased is compared to the concentration of drug in the drug core witha least square regression line. For the 0.006, 0.012 and 0.025 inch drugcores the slope of the regression lines are 3.0, 4.3 and 2.2,respectively. For the 0.012 and 0.025 inch cores, these values indicatethat a doubling of concentration of the Latanoprost drug in the coredoes not lead to a doubling of the elution rate of the Latanoprost fromthe core, consistent with droplets of Latanoprost suspended in a drugcore matrix and substantial saturation of the drug core matrix withLatanoprost dissolved therein, as described above. However, for the0.006 inch diameter core, there is an approximately first orderrelationship between the quantity of initially in the core and theamount of drug released at day 14, which can may be caused by depletionof Latanoprost drug droplets in the core.

FIGS. 7D and 7E show dependence of the rate of elution on exposedsurface area of the drug core for the three core diameters and the threeconcentrations as in FIGS. 7A and 7B Latanoprost at day 1 and day 14,respectively, according to embodiments of the present invention. Elutionrate of the Latanoprost in nanograms (ng) per day is plotted versus theexposed surface area of the drug core in mm2 as determined by thediameter of the drug core. These data show that the rate of elution ismildly dependent on the concentration of drug in the core and stronglydependent on the exposed surface area at both one day and a 14 days. Theexposed surface areas of the 0.006 inch, 0.012 inch and 0.025 inchdiameter cores are approximately 0.02, 0.07, and 0.32 mm2, respectively.At day 1, the 0.02, 0.07, and 0.32 mm2, cores released about 200 ng, 400ng and 1200 ng of Latanoprost, respectively, showing that the quantityof Latanoprost released increases with an increased size of the exposedsurface area of the drug core. For each concentration of therapeuticagent in the drug core, the quantity of Latanoprost released is comparedto the exposed surface area of the drug core with a least squareregression line. For the 5.1%, 11.2%, and 17.9% drug cores the slope ofthe regression lines are 2837.8, 3286.1 and 3411.6, respectively, withR2 coefficients of 0.9925, 0.9701 and 1, respectively. At day 14, the0.02, 0.07, and 0.32 mm2, cores released about 25 ng, 100 ng and 300 ngof Latanoprost, respectively showing that the quantity of Latanoprostreleased increases with an increased size of the exposed surface area ofthe drug core. For the 5.1%, 11.2%, and 17.9% drug cores the slope ofthe regression lines are 812.19, 1060.1 and 764.35, respectively, withR2 coefficients of 0.9904, 0.9924 and 0.9663, respectively. These valuesindicate the elution rate of the Latanoprost from the core increaseslinearly with the surface area of the drug core, consistent with a drugsheath that can control the exposed surface area, as described above.The weak dependence of Latanoprost elution on concentration in the drugcore is consistent with droplets of Latanoprost suspended in a drug corematrix and substantial saturation of the drug core matrix withLatanoprost dissolved therein, as described above.

FIG. 7C shows elution data for Latanoprost from 0.32 mm diameter, 0.95mm long drug cores with concentrations of 5, 10 and 20% and drug weightsof 3.5, 7 and 14 μg, respectively, according to embodiments of thepresent invention. The drug cores were manufactured as described above.The elution rate is plotted in ng per day from 0 to 40 days.

The 14 μg core shows rates of approximately 100 ng per day from about 10to 40 days. The 7 μg core shows comparable rates from 10 to 20 days.These data are consistent with droplets of Latanoprost suspended in adrug core matrix and substantial saturation of the drug core matrix withLatanoprost dissolved therein, as described above.

Table 2 shows the expected parameters for each drug concentration. Asshown in FIG. 7C, in vitro results in a buffered saline elution systemshow that the plug initially elutes approximately 500 ng of Latanoprostper day, dropping off rapidly within 7-14 days to approximately 100ng/day, depending on the initial concentration of drug.

TABLE 2 Drug Elution Properties Total Latanoprost content 14 μg 7 μg 3.5μg In vitro elution rate See FIG. 7C See FIG. 7C See FIG. 7C Duration~100 days ~45 days ~25 days

In many embodiments, the duration of the drug core can be determinedbased on the calculated time when ˜10% of the original amount of drugremains in drug insert, for example where the elution rate levels outand remains substantially constant at approximately 100 ng/day.

Example 2 Cyclosporin Drug Core Elution Data

Drug cores as described in Example 1 were made with cyclosporin having aconcentration of 21.2%. FIG. 8A shows elution profiles of cyclosporinfrom drug cores into a buffer solution without surfactant and into abuffer solution with surfactant, according to embodiments of the presentinvention. The buffer solution was made as described above. The solutionwith surfactant includes 95% buffer and 5% surfactant, UP-1005 UltraPure Fluid from Dow Corning, Midland Mich. Work in relation withembodiments of the present invention indicates that in at least someinstances, surfactants may be used in in vitro to model in situ elutionfrom the eye as the eye can include natural surfactants, for exampleSurfactant Protein D, in the tear film. The elution profile ofcyclosporin into surfactant is approximately 50 to 100 ng per day from30 to 60 days. Empirical data from tears of a patient population, forexample 10 patients, can be measured and used to refine the in vitromodel with appropriate amounts of surfactant. The drug core matrix maybe modified in response to the human tear surfactant as determined withthe modified in vitro model. The drug core can be modified in many waysin response to the human tear film surfactant, for example with anincreased exposed surface area and/or additives to increase an amount ofcyclosporine drug dissolved in the core, as described above, to increaseelution from the core to therapeutic levels, if appropriate.

Example 3 Bimatoprost Bulk Elution Data

Bulk samples of 1% Bimatoprost having a known diameter of 0.076 cm (0.76mm) were prepared. The height of each sample was determined from theweight and known diameter of the sample.

TABLE 3 Bulk Sample Size Diameter calculated Exposed Surface Sample wt(mg) (cm) height (cm) Area (cm{circumflex over ( )}2) 14-2-10 1.9 0.0760.42 0.109 14-2-11 1.5 0.076 0.33 0.088 14-2-12 1.9 0.076 0.42 0.109

The calculated heights ranged from 0.33 cm to 0.42 cm. The exposedsurface area on each end of each bulk sample was approximately 0.045cm2, providing volumes of 0.019 cm3 and 0.015 cm3 for the 0.42 and 0.33cm samples, respectively. The exposed an exposed surface area of samplescalculated from the height and diameter without a drug sheath wasapproximately 0.1 cm2. Three formulations were evaluated: 1) silicone4011, 1% Bimatoprost, 0% surfactant; 2) silicone 4011, 1% Bimatoprost,approximately 11% surfactant; and 3) silicone 4011, 1% Bimatoprost,approximately 33% surfactant. The elution data measured for the bulksamples with formulation 1, 2 and 3 were normalized to ng per device perday (ng/device/day) assuming a surface area of the bulk device is 0.1cm2 and the surface area of the clinical device is 0.00078 cm2 (0.3 mmdiameter). FIG. 9A shows normalized elution profiles in ng per deviceper day over 100 days for bulk sample of silicone with 1% Bimatoprost,assuming an exposed surface diameter of 0.3 mm on the end of the device,according to embodiments of the present invention. The normalizedelution profile is about 10 ng per day. The data show approximately zeroorder release kinetics from about ten days to about 90 days for each ofthe formulations. These data are consistent with particles ofBimatoprost suspended in a drug core matrix and substantial saturationof the drug core matrix with Bimatoprost dissolved therein, as describedabove. Similar formulations can be used with drug core sheaths and ashaped exposed surface of the core exposed to the tear to increase theexposed surface area as described above and deliver the drug intherapeutic amounts over an extended period.

In some embodiments, the core can comprise a 0.76 mm diameter core withan exposed surface diameter of 0.76 mm, corresponding to an exposedsurface area of 0.0045 cm2. The core can be covered with a sheath todefine the exposed surface of the core as described above The normalizedelution profile for such a device, based on the bulk sample data above,is approximately 6 times (0.0045 cm2/0.00078 cm2) the elution profilefor the device with a 0.3 mm diameter exposed surface area. Thus, a zeroorder elution profile with an elution rate of about 60 ng per day can beobtained over a period of about 90 days. If the exposed surface area isincreased to about 0.0078 cm2, for example with many of the exposedsurface shapes as described above, the zero order elution rat is about100 ng per day over a period of about 90 days. The concentration canalso be increased from 1%. Similar elution profiles can be obtained withLatanoprost.

Example 4 Latanoprost Elution Data

Drug cores were manufactured as described above in Example 1 withLatanoprost and silicone 4011, 6385 and/or NaCl. Four formulations weremanufactured as follows: A) silicone 4011, approximately 20%Latanoprost, and approximately 20% NaCl; B) silicone 4011, approximately20% Latanoprost, and approximately 10% NaCl; C) silicone 4011,approximately 10% Latanoprost, and approximately 10% NaCl; and D)silicone 6385, approximately 20% Latanoprost. FIG. 10A shows profiles ofelution of Latanoprost form the cores for four formulations ofLatanoprost, according to embodiments of the present invention. Theresults show initial rates of approximately 300 ng per device per daythat decreases to about 100 ng per device per day by 3 weeks (21 days).The results shown are for non-sterile drug cores. Similar results havebeen obtained with sterile drug cores of Latanoprost. These data areconsistent with droplets of Latanoprost suspended in a drug core matrixand substantial saturation of the drug core matrix with Latanoprostdissolved therein, as described above.

Example 5 Drug Release as a Function of Cros Slinking

FIG. 11A shows the effect on elution of material and crosslinking ondrug cores with 20% latanoprost, according to embodiments of the presentinvention. Drug cores were manufactured as described above withmanufacturing methods as in FIG. 6E and Table 1. The drug corescomprised 4011 silicone, 6385 silicone with 2.5% crosslinker, 6380 with2.5% crosslinker and 6380 with 5% crosslinker. The therapeutic agent inall samples comprised approximately 20% latanoprost. The 6380 materialwith 5% crosslinker provided the lowest elution rate at all time points.As the 6380 material with 5% crosslinker elutes at a lower rate than the6385 material with 2.5% crosslinker, increased crosslinker andconcomitant crosslinking appears to decrease the rate of elution. The6385 material with 2.5% crosslinker provides the highest elution ratesat 1, 4, 7 and 14 days. The 6380 material with 2.5% crosslinker hasslightly lower elution rate at 1, 4, 7 and 14 days than the 6385material. Both the 6385 and 6380 materials elute faster than the 4011material that does not include a filler material. The 4011, 6380 and6385 materials comprise dimethyl siloxane as the base polymer. As notedabove, the 6385 material comprises diatomaceous earth filler material,and the 6380 material comprises silica filler material, indicating,based on the above elution rates, that the inert filler material canincrease the rate of elution.

Example 6 Effect of Drug Concentration on the Elustion of Latanoprost

FIG. 11B shows the effect of drug concentration on the elution oflatanoprost, according to embodiments of the present invention. Drugcores were manufactured as described above with manufacturing methods asin FIG. 6E and Table 1. The drug cores comprised 6385 material with 5,10, 20, 30 and 40% latanoprost, respectively. The amount of tin-alkoxycure system was 2.5% in all samples. The release of latanoprost isweakly dependent on the concentration of latanoprost at all time periodswith 40% the latanoprost Material eluting at the highest rate and 5%latanoprost eluting at the lowest rate. The elution rate for all samplesfalls below 500 ng per day by 7 days and continues to be released attherapeutic levels thereafter.

Example 7 Effect of Covering One End of the Drug Core Insert

FIG. 11C shows the effect of covering one end of the drug core insert,according to embodiments of the present invention. Drug cores weremanufactured as described above with manufacturing methods as in FIG. 6Eand Table 1. The drug cores comprised 6385 material with 20%latanoprost. The elution rate of cut tubes as described above wasmeasured with both ends of each cut tube open, referred to as both endsopen. The elution rate of cut tubes with one end exposed and one endcovered with uv cured Loctite, as described above, was measured,referred to as one end open. For comparison, the elution rate for thedrug core inserts with both ends open divided by two is shown, referredto as “both ends open/2”. The both ends open/2 values are very close tothe one end open data at all time points, indicating that covering oneend of the drug core insert with an adhesive material that issubstantially impermeable to the therapeutic agent can inhibit therelease of therapeutic agent from the drug core, such that the drug iseffectively delivered through the exposed surface of the drug core onthe open end of the tube.

Example 8 Elution of Fluorescein and the Effect of Surfactant onFluorescein Elution

FIG. 12A shows the elution of fluorescein and the effect of surfactanton fluorescein elution, according to embodiments of the presentinvention. The elution data for fluorescein show the flexibility of theabove drug core and manufacturing processes for the sustained release ofmany therapeutic agents, including both water soluble and waterinsoluble therapeutic agents, and relatively low molecular weight andhigh molecular weight therapeutic agents. Fluorescein has a molecularmass of 332.32 g/mol, is soluble in water, and can serve as a model forthe release water soluble therapeutic agents released from the eye. Workin relation with embodiments of the present invention indicates thatmolecular weight and solubility in water can each effect the releaserate of the drug from the solid drug core matrix. For example, lowermolecular weight may increase diffusion through the solid matrixmaterial, i.e. through silicone, such that low molecular weightcompounds may be released more quickly. Also, solubility in water canalso effect the release rate of the drug, and in some instancesincreased water solubility of the drug may increase the rate of releasefrom the solid drug core matrix, for example via transport from thesolid matrix material to the bodily liquid, such as tear liquid. Inaccordance with these embodiments, therapeutic agents with highermolecular weight than fluorescein and with lower water solubility thanfluorescein, for example cyclosporin and prostaglandins as shown above,may be released from the solid core at lower rates. Surfactants may alsoeffect the rate of release of the therapeutic agent from the drug coreinto the surrounding bodily tissue and/or fluid, for example tear filmfluid.

Each drug core tested comprised MED 4011 silicone. In one embodiments, adrug core formulation 1210 comprised 9% surfactant and 0.09%fluorescein. An exponential fit 1212 is shown for the elution rate ofdrug core formulation 1210. In another embodiment, a drug coreformulation 1220 comprised 16.5% surfactant and 0.17% fluorescein. Anexponential fit 1222 is shown for the elution rate of drug coreformulation 1220. In another embodiment, a drug core formulation 1230comprised 22.85% surfactant and 0.23% fluorescein. An exponential fit1232 is shown for the elution rate of drug core formulation 1230. In anembodiment without surfactant, a drug core formulation 1240 comprised 0%surfactant and 0.3% fluorescein. An exponential fit 1242 is shown forthe elution rate of drug core formulation 1240.

The drug cores were manufactured with key formulations comprising:Silicone Surfactant “190 Fluid” (Dow Coming); Surfactant Mix: “190Fluid” +Fluorescein; Silicone (Nusil): MED 4011 Part A, MED 4011 Part B;Centrifuge Tubes; 3 mL Syringe; 20 ga. Needle; 0.031 inch inner diameterTeflon Tube; and Buffer.

Key parameters included: Prepare a mixture of 2.5 g of siliconesurfactant and 0.025 g of fluorescein; Prepare silicone compositions ofNusil MED 4011 containing 3.5 g Part A and 0.37 g Part B (10:1 ratio);Prepare four (4) centrifuge tubes each with 0.5 g of silicone andvarying surfactant mixture weights as follows: A. 0.05 g surfactant mix:9% surfactant, 0.09% fluorescein; B. 0.1 g surfactant mix: 16.5%surfactant, 0.17% fluorescein; C. 0.15 surfactant mix: 22.85%surfactant, 0.23% fluorescein; D. 0.0015 g fluorescein: 0% surfactant,0.3% fluorescein; Inject each of the four formulations into respectiveteflon tubes using the syringe and needle; Cure the injected tube at140° C. for 45 minutes in the oven; Cut each tube into 3 pieces inlength to 4 mm; and Immerse each cut piece into a centrifuge tubecontaining 0.3 mL of buffer.

Data collection comprised: Collect samples at time points 24, 48, 72,192, and 312 hours; Submit each sample for UV spectrometry analysis;Convert each elution rate from μg/mL/hr to μg/cm2/hr by using thedimensions of the teflon tube (4 mm length, 0.031 inch inner diameter);Plot data for elution rate vs. time to compare the rates of eachsurfactant mix formulation.

Analysis comprised fitting trendlines for each elution rate to anexponential curve, as shown in Table 4.

TABLE 4 Trendlines for each elution rate fit to exponential curves.Sample # % Surfactant % Fluorescein R2 Trendline Equation A 9.0 0.090.9497 636.66x-1.1161 B 16.5 0.17 0.8785 4289.6x-1.3706 C 22.85 0.230.9554 1762.0x-1.0711 D 0 0.30 0.9478 1142.1x-1.2305

The trendline equations of table 4 indicate the following: The data fitexperimental curves well with R2 values of 0.8785 to 0.9554. Thetrendline equations shows exponent coefficients of −1.0711 to −1.3706.Elution rates increased with increasing surfactant levels. Despiterelatively similar amounts of fluorescein, there is a dramatic increasein elution rates between Samples C and D—this demonstrates that theaddition of surfactant to the silicone matrix dramatically affects theelution rate of the water-soluble compound. The elution rate of Sample Ais comparable to that of Sample D, even though Sample A contains onlyone-third the amount of fluorescein. This also demonstrates that therate of elution can be affected by the addition of surfactant to thesilicone matrix.

Although the trendline equation exponent coefficients of −1.071 1 to−1.3706 are consistent with first order release, the data include aninitial 48 hour period in which bolus release of fluorescein from thecore is observed. Such an initial washout period of 2 to 3 days withhigh levels of the therapeutic agent delivered followed by a period ofsustained release at therapeutic levels can be helpful in someembodiments, for example where elevated levels for a short period oftime are tolerated and can lead to an accelerated effect on the eye.Work in relation with embodiments of the present invention suggests thatafter 48 hours the elution data can be closer to zero order, for examplewithin a range from about zero order to about first order. In someembodiments, the level of release therapeutic agent can be decreasedwith a decreased exposed surface area of the drug core, for example asdescribed above, to release the drug at therapeutic levels for sustainedperiods.

Example 9 The Effect of Sterilization on Elution of Therapeutic Agent

Work in relation to embodiments of the present invention suggests thatradicals generated in the sterilization process may crosslink the drugcore matrix material so as to inhibit the initial release rate oftherapeutic agent from the drug core matrix material. In specificembodiments with e-beam sterilization, this cross-linking may be limitedto the surface and/or near the surface of the drug core matrix. In someembodiments, a known Mylar bag can be penetrated with the e-beam tosterilize the surface of the drug core. In some embodiments, othersterilization techniques that effect sterilization can be used, forexample gamma ray sterilization, and that are not limited to the surfaceof the drug core and fully and/or uniformly penetrate the drug corematerial.

Drug cores were synthesized and e-beam sterilized in Mylar packaging, asdescribed above. FIG. 13A shows the elution of sterilized andnon-sterilized drug cores. The sterile and non-sterile drug cores eachcomprised 20% latanoprost in 6385 synthesized as described above. Thedrug cores were e-beam sterilized and the elution rates measured asdescribed above. The sterile and non-sterile drug cores show elutionrates for the first day of about 450 and 1400 ng/day, respectively. Atdays 4 and 7, the sterile and non-sterile drug cores show similarelution rates at about 400 ng/day. At 14 day the sterile and non-steriledrug cores show elution rates of 200 and about 150 ng/day, respectively.These data show that sterilization may decrease an initial release, orbolus, of the therapeutic agent, and that sterilization may be used toprovide a more uniform rate of release of the therapeutic agent, forexample in combination with embodiments described above.

Example 10 The Effect of Salt on Elution of Therapeutic Agent

Work in relation to embodiments of the present invention suggests thatknown salts, for example sodium chloride can effect the rate of elutionfrom the drug core.

FIG. 14A shows the effect of salt on the elution of therapeutic agent.Drug cores comprising 20% bimatoprost (BT) and silicone drug core matrixcomprising NuSil 6385 were manufactured as described above. Drug coreswere manufactured with salt concentrations of 0%, 10% and 20%. At 1 daythe drug cores showed elution rates of about 750 ng/day, 400 ng per dayand about 100 ng per day for 20%, 10% and 0%, respectively. At all timeperiods measured to two weeks, the 20% salt data showed the highestelution rate and the 0% salt data showed the lowest elution rate. Thisdata shows that salt, for example many known salts such as sodiumchloride, can be added to the matrix to increase the order of theelution rate of therapeutic agent.

Example 11

Extraction of Therapeutic Agent from Drug Cores to Determine TherapeuticAgent Yield

Drug core inserts comprising MED-6385 and 20% and 40% latanoprost weresynthesized as described above. Each drug core was weighed and theweight of solid drug core material determined with correction for theweight of the drug tube and adhesive. The amount of therapeutic agentpresent in each sample was determined based on the weight of drug corematerial and percentage of therapeutic agent in the drug core materialas described above. The therapeutic agent was extracted from the drugcores with 1 ml aliquots of methyl acetate. The concentration oftherapeutic agent in the solution for each sample was measured withreverse phase gradient HPLC with optical detection and peak integrationat 210 nm. Measurements were taken for 6 drug cores with 20% latanoprostand 4 drug cores with 40% latanoprost. For the 20% samples, the averageextraction of latanoprost was 104.8% with a standard deviation of about10%. For the 40% samples, the average extraction of latanoprost was96.8% with a standard deviation of about 13%.

Example 12 High Pressure Filling

A two part silicone formulation (MED6385, Nusil Technologies) was usedin the preparation of a composite resin containing latanoprost, whichwas used to fill a section of polyimide sheathing. The sheathingcontaining the polymerized silicone incorporates discrete latanoprostdomains, existing in the form of droplets of less than about 25 μmmaximum diameter, within the matrix. Several experiments were conducted.

Part A of the MED6385 silicone formulation was mixed with 0.43 μL ofPart B, the tin catalyst, using syringes, to bring about partialcoagulation of the polymer over 30 minutes. Then, 37 mg of that materialwas mixed with a premixed solution of 0.144 additional catalyst and 13mg latanoprost, and that mixture could be further mixed by sonicationwith an ultrasonic probe. The resulting mixture was transferred to asyringe needle connected to a HP7× syringe adapter, which is connectedto an EFD pump, which is in turn connected to a compressed air systemand the delivery pressure set to 40 psi. The silicone-latanoprostmixture is then extruded down the length (10 cm) of polyimide tubing(IWG High Performance Conductors, Inc.). When the viscous mixturereached the bottom of polyimide tubing, clamps were applied at thebottom of the tubing and at the top connection with the syringe adapter,then pressure is released and the tubing section removed. The clampedsection of tubing was placed in a humidity chamber (Thunder Scientific)for curing at 40° C. and 80% relative humidity (RH) for approximately16-24 hrs.

To process the filled polyimide tubing containing the now-solid matrixcontaining the latanoprost into individual drug inserts, the filledprecursor sheath was then cut into 1 mm segments with a jig and a razorblade. One end of each of the 1 mm segments was then sealed with Loctite4305 UV Flash cure adhesive, and cured with a Loctite UV wand. Each ofthe segments at this point was ready for insertion into a punctal plug(Quintess) adapted to receive the insert, sealed end inward.

Results

Scanning electron micrographs of the sheath containing the cured matrix,i.e., the filled precursor sheath, are shown in FIG. 15A-D at themagnifications indicated. The inserts were sectioned cryogenically.FIGS. 15A and 15B, respectively, show the insert cores wherein theextrusion was carried at 40° C. (A) or 25° C. (B).

Example 13

The temperature of the mixture, and of the associated apparatus involvedin filling the polyimide sheath was held at various temperatures duringthe injection process. Among the temperatures used were a slightlyelevated temperature (40° C.), approximate room temperature (25° C.),and subambient temperatures, such as 0° C., −5° C., and −25° C. Thesubambient injection procedures are provided in this Example.

Manufacture of Latanprost/Silicone Mixture

The silicone formulation (MED6385) is a two part system. Part A containsthe silicone and crosslinker while Part B contains the tin catalyst topromote crosslinking. The two parts are combined in a final ratio of200:1 (Part A:Part B). The required amounts of Latanoprost, MED6385 PartA and B are weighed onto a glass slide and mixed for approximately 2minutes using a plastic mini spatula. The weight or volume of componentsrequired to prepare 50 mg of mixture to be extruded is presented in theTable below.

Ratio of Components

Strength (μg latanoprost/′plug) Part A (mg) Part B (μl) Latanoprost (mg)3.5 47.8 0.21 2.2 14 41.1 0.18 8.9 21 36.7 0.16 13.3Extrusion into Polyimide Tubing

Preparation of Syringe Extrusion System

15 cm sections are threaded through a plastic luer adaptor and glued inplace using Loctite 4304 UV flash cure adhesive (FIG. 2). A 1 mL syringe(Henke Sass Wolf NORMJect) is modified by cutting the tip of the plungerflush. The previously assembled tubing/adaptor piece is inserted intothe syringe barrel and threaded through the luer outlet and fitted inplace.

Extrusion

After the silicone/latanoprost mixing is complete, the mixture is loadedin the barrel of the syringe extrusion system. The plunger is insertedand excess air is removed. The syringe is then ready to be loaded intothe chilled extrusion apparatus. The apparatus is an all stainless steeljacketed tube in a tube sanitary welded heat exchanger and includes agas purge that is internally cooled by coiling inside the coolant sideof the heat exchanger. The operating temperature setpoint of the coolingsystem shall be −10° C. The temperature inside the heat exchanger shallbe uniform +/−2.5° C. over the useable length of the polyimide tubing.The steady state temperature of the cooling system is to be verifiedprior to insertion of syringe and tubing.

After setup, the EFD is activated and a silicone latanoprost mixture isextruded down the length of the polyimide tubing. Once the mixturereaches the bottom of the tubing, it can be visually detected. Thesyringe including tubing is quickly removed from the cooling system. Thesyringe is removed by cutting the tubing with a razor blade; then thetubing is clamped on both ends.

Curing

The clamped section of tubing is placed in a humidity chamber (ThunderScientific) to be cured at 40° C. and 80% RH for approximately 16-24hours.

Results

Scanning electron micrographs of the sheath containing the cured matrix,i.e., the filled precursor sheath, are shown in FIG. 15A-D at themagnifications indicated. The inserts were sectioned cryogenically.FIGS. 15C and 15D show the results of extrusions carried out at 0° C.and −25° C. respectively. They can be compared with FIGS. 15A and 15Bthat were carried out at ambient temperature (25° C.) or above (40° C.).

Measurements of average inclusion diameters, and standard deviationthereof, are as shown:

Cold extrusion (−5° C.): 0.006±0.002 mm (n=40 inclusion)

Room temp (22° C.): 0.019±0.019 mm (n=40 inclusion)

Measurements of average latanoprost content (μg) per 1 mm section (core)divided (razor blade) from a filled precursor tube are as shown:

Cold extrusion (−5° C.): 20.9±0.5 (Average±SD) RSD=2.4

Room temperature (22° C.): 20.2±1.9 (Average±SD) RSD=9.4

Further Embodiments

While described above primarily with reference to treatment of an eye,embodiments of the drug release structures described herein may alsofind applications for treatment of a wide variety of tissues to treat arange of differing disease states. In some embodiments, these structuresmay be used for systemic and/or (more commonly) localized elution of atherapeutic agent to treat cancer. In embodiments used for chemotherapy,the matrix may be configured to release of a therapeutic cocktail thatis dependent upon the primary tumor type. Use of a local delivery may beparticularly beneficial for treating a tumor site post-surgically, andmay help minimizing side effects and collateral damage to healthytissues of the body. In some embodiments, a lumpectomy for breast tumorand/or or surgical treatment of prostate cancer can be treated. In manyembodiments, a tumor is targeted with positioning of the matrix withinand/or adjacent the targeted tumor. In some embodiments, the implant maycomprise a radioactive agent to treat the tumor in combination with thetherapeutic agent.

Still further alternative embodiments may facilitate elution of atherapeutic agent into a tissue of an ear, into a mouth, into a urethra,into a skin, into a knee joint (or other joint) of a patient, or thelike. Conditions of joints that can be treated include arthritis andother joint diseases, and the therapeutic agents that may be used maycomprise (for example) at least one COX II inhibitor, NSAIDs, and/or thelike. Such localized use of NSAIDs and COX II inhibitors may reduce therisks associated with systemic use of these compounds. In someembodiments, the matrix may comprise nutritional supplements likeglucosamine to effect a positive physiological response in local tissueof and/or near the joint. Implants for elution of therapeutic agentsinto or adjacent an intervertebral joint may be particularlyadvantageous. Similar (or other) pain relievers, antibiotics,antimicrobials, and/or the like may also be included in an implant forelution of one or more therapeutic agent into a localized trauma.Implants (optionally implants having structures derived from thepunctual implants described above may allow elution of one or moretherapeutic agent into a nasal cavity. Modifications or differencesbetween such nasal implants and the punctual implants described abovemay include providing a passage for controlled release of medicated tearfluid through the canilicular lumen. Alternative nasal tissue structuresmay be quite different in overall form, optionally including any of avariety of known nasal cavity drug release shapes, but optionally takingadvantage of one or more aspects of the drug cores or other drug releasestructures described above for long term release of one or moreappropriate therapeutic agents.

Still further alternative embodiments find application in cosmetic uses.For example, these uses include administration of a prostaglandin toenhance eye lash growth. p While the exemplary embodiments have beendescribed in some detail, by way of example and for clarity ofunderstanding, those of skill in the art will recognize that a varietyof modification, adaptations, and changes may be employed. For example,multiple delivery mechanisms may be employed, and each device embodimentmay be adapted to include features or materials of the other, andfurther multiple features or multiple materials may be employed in asingle device. Hence, the scope of the present invention may be limitedsolely by the appending claims.

1-41. (canceled)
 42. An ocular implant for topical delivery of at leastone therapeutic agent to an eye for an extended period of time,comprising: a substantially cylindrical shaped body; a therapeuticmatrix comprising a therapeutic agent and a polymer, wherein at least aportion of the therapeutic matrix is exposed to tear fluid and thetherapeutic agent is uniformly and homogenously dispersed throughout thematrix; wherein the body is adapted to release the therapeutic agent attherapeutic levels into the tear fluid of the eye for at least one monthand wherein the ocular implant is configured to be placed betweenconjunctiva tissue in a cul-de-sac of the eyelid and does not comprise asheath body.
 43. The implant of claim 42, wherein the polymer comprisessilicone or urethane.
 44. The implant of claim 42, wherein thetherapeutic agent is an anti-glaucoma agent, a prostaglandin analog, aprostaglandin, an antimicrobial agent, an anti-inflammatory agent, or anallergy medication.
 45. The implant of claim 42, when placed in thecul-de-sac of the eyelid treats conditions selected from glaucoma, pre-and post-surgical treatments, dry eye, allergies, pain, conjunctivitis,infection, and inflammation.
 46. The implant of claim 42, wherein thetherapeutic agent is latanoprost, bimatoprost, travoprost or Timolol.47. The implant of claim 42, wherein the body comprises a shape memorypolymer.
 48. The implant of claim 42, wherein the body comprisesacrylates, polyethylenes, polyurethane, hydrogel, polyester,polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE),polyether ether ketone (PEEK), nylon, extruded collagen, polymer foam,silicone rubber, polyethylene terephthalate, ultra high molecular weightpolyethylene, polycarbonate urethane, polyimides, stainless steel,nickel-titanium alloy, titanium, stainless steel, or cobalt-chromealloy.
 49. The implant of claim 42, wherein the therapeutic agent isbimatoprost formulated for extended release of 3 to 6 months.
 50. Theimplant of claim 42, wherein the therapeutic agent is bimatoprostformulated for extended release of 6 to 12 months.
 51. The implant ofclaim 42, wherein the therapeutic matrix further comprises an additiveto increase solubility of the therapeutic agent in the matrix.
 52. Theimplant of claim 42, wherein the body has a circular cross section. 53.The implant of claim 42, wherein the matrix comprises anon-biodegradable polymer.
 54. A composition comprising a polymer matrixand a therapeutic agent, wherein the therapeutic agent is uniformly andhomogenously dispersed in the matrix and wherein the composition isadapted to release the therapeutic agent at therapeutic levels to theeye for at least one month and wherein the composition is configured tobe placed between conjunctiva tissue in a cul-de-sac of the eyelid anddoes not comprise a sheath body, and wherein the composition comprises acircular cross section.
 55. The composition of claim 54, wherein thecomposition is configured as a medical device.
 56. The composition ofclaim 54, wherein the composition is configured to be placed in contactwith tear fluid.
 57. The composition of claim 54, wherein the polymermatrix comprises a non-biodegradable polymer.
 58. The composition ofclaim 54, wherein the therapeutic agent is an anti-glaucoma agent, aprostaglandin analog, a prostaglandin, an antimicrobial agent, ananti-inflammatory agent, or an allergy medication.
 59. The compositionof claim 54, when placed in the cul-de-sac of the eyelid treatsconditions selected from glaucoma, pre- and post-surgical treatments,dry eye, allergies, pain, conjunctivitis, infection, and inflammation.60. The composition of claim 58, wherein the anti-glaucoma agent islatanoprost, travoprost or Timolol.
 61. The composition of claim 58,wherein the anti-glaucoma agent is bimatoprost.
 62. The composition ofclaim 54, wherein the polymer comprises silicone or urethane.
 63. Thecomposition of claim 54, wherein the polymer comprises acrylates,polyethylenes, polyurethane, hydrogel, polyester, polypropylene,polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyether etherketone (PEEK), nylon, extruded collagen, polymer foam, silicone rubber,polyethylene terephthalate, ultra high molecular weight polyethylene,polycarbonate urethane, polyimides, stainless steel, nickel-titaniumalloy, titanium, stainless steel, or cobalt-chrome alloy.
 64. Thecomposition of claim 54, wherein the polymer matrix comprises hydrogel,polyglycolic acid (PGA), polylactic acid (PLA), poly(L-lactic acid)(PLLA), poly(L-glycolic acid) (PLGA), polyglycolide, poly-L-lactide,poly-D-lactide, poly(amino acids), polydioxanone, polycaprolactone,polygluconate, polylactic acid-polyethylene oxide copolymers, modifiedcellulose, collagen, polyorthoesters, polyhydroxybutyrate,polyanhydride, polyphosphoester, poly(alpha-hydroxy acid) orcombinations thereof.
 65. The composition of claim 54, comprises asubstantially cylindrical shape.
 66. An ocular implant for topicaldelivery of at least one therapeutic agent to an eye for an extendedperiod of time, comprising: a substantially cylindrical shaped body; atherapeutic matrix comprising an anti-glaucoma agent and a polymer,wherein at least a portion of the therapeutic matrix is exposed to tearfluid and the anti-glaucoma agent is uniformly and homogenouslydispersed throughout the matrix; wherein the body is adapted to releasethe anti-glaucoma agent at therapeutic levels into the tear fluid of theeye for at least one month and wherein the ocular implant is configuredto be placed between conjunctiva tissue in a cul-de-sac of the eyelidand does not comprise a sheath body.
 67. The implant of claim 66,wherein the anti-glaucoma agent is latanoprost, travoprost or Timolol.68. The implant of claim 66, wherein the anti-glaucoma agent isbimatoprost.